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1.  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.
doi:10.1164/rccm.201204-0713OC
PMCID: PMC3622444  PMID: 23087028
sepsis; emergency medical services; epidemiology
2.  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.
doi:10.1164/rccm.201111-2025OC
PMCID: PMC3381234  PMID: 22492988
acute respiratory distress syndrome; acute lung injury; cognitive function; critical illness
3.  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.
doi:10.1164/rccm.201002-0301OC
PMCID: PMC3159078  PMID: 21057004
Medicare; intensive care; mechanical ventilation; quality of life; functional status
4.  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.
doi:10.1164/rccm.200904-0630CP
PMCID: PMC2970850  PMID: 20558632
critical care; elderly; aging
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.
doi:10.1164/rccm.200712-1777OC
PMCID: PMC2720087  PMID: 18369199
cytokines; mortality; pneumonia; IL-6; IL-10
6.  Potential Value of Regionalized Intensive Care for Mechanically Ventilated Medical Patients 
Rationale: Regionalization has been proposed as a method to improve outcomes for medical patients receiving mechanical ventilation in the intensive care unit.
Objectives: To determine the number of patients who would be affected by regionalization and the potential mortality reduction under a regionalized system of care.
Methods: We performed a retrospective cohort study with Monte Carlo simulation, using 2001 state discharge data from eight states representing 42% of the U.S. population. Adult medical patients undergoing invasive mechanical ventilation were identified. Patient location and hospital mortality rates were obtained from the discharge data; estimates of the relative risk reduction in hospital mortality for high-volume hospitals compared with low-volume hospitals were obtained from the published literature and applied to the cohort.
Measurements and Main Results: Of 180,976 adult medical patients who underwent mechanical ventilation at 1,170 nonfederal hospitals, 83,050 (46%) received mechanical ventilation at 887 (76%) hospitals with low annual volumes (fewer than 275 patients per year). Using published risk estimates, approximately 4,720 lives per year (95% range, 2,522–6,744) could potentially be saved in the 8 states by routinely transferring patients from low- to high-volume hospitals, representing a number needed to treat of 15.7. The median distance that patients would need to travel to reach a high-volume hospital was 8.5 miles (interquartile range, 4.0–21.2 mi).
Conclusions: Regionalization of intensive care could potentially improve survival for patients undergoing mechanical ventilation. Transfer distances are modest for most patients.
doi:10.1164/rccm.200708-1214OC
PMCID: PMC2218846  PMID: 18006884
mechanical ventilation; triage; transportation of patients; critical care; Monte Carlo method
7.  Racial Variation in the Incidence, Care, and Outcomes of Severe Sepsis 
Rationale: Higher rates of sepsis have been reported in minorities.
Objectives: To explore racial differences in the incidence and associated case fatality of severe sepsis, accounting for clinical, social, health care service delivery, and geographic characteristics.
Methods: Retrospective population-based cohort study using hospital discharge and U.S. Census data for all persons (n = 71,102,655) living in 68 hospital referral regions in six states.
Measurements and Main Results: Age-, sex- and race-standardized severe sepsis incidence and inpatient case fatality rates, adjusted incidence rate ratios, and adjusted intensive care unit (ICU) admission and case fatality rate differences. Of 8,938,111 nonfederal hospitalizations, 282,292 had severe sepsis. Overall, blacks had the highest age- and sex-standardized population-based incidence (6.08/1,000 vs. 4.06/1,000 for Hispanics and 3.58/1,000 for whites) and ICU case fatality (32.1 vs. 30.4% for Hispanics and 29.3% for whites, P < 0.0001). Adjusting for differences in poverty in their region of residence, blacks still had a higher population-based incidence of severe sepsis (adjusted rate ratio, 1.44 [95% CI, 1.42–1.46]) than whites, but Hispanics had a lower incidence (adjusted rate ratio, 0.91 [0.90–0.92]). Among patients with severe sepsis admitted to the ICU, adjustments for clinical characteristics and the treating hospital fully explained blacks' higher ICU case fatality.
Conclusions: Higher adjusted black incidence and the lower Hispanic incidence may reflect residual confounding, or it could signal biologic differences in susceptibility. Focused interventions to improve processes and outcomes of care at the hospitals that disproportionately treat blacks could narrow disparities in overall mortality from severe sepsis.
doi:10.1164/rccm.200703-480OC
PMCID: PMC2720103  PMID: 17975201
severe sepsis; epidemiology; race; clinical practice variations
8.  4G/5G Plasminogen Activator Inhibitor-1 Polymorphisms and Haplotypes Are Associated with Pneumonia 
Rationale: Plasminogen activator inhibitor (PAI)-1 inhibits urokinase and tissue plasminogen activator, required for host response to infection. Whether variation within the PAI-1 gene is associated with increased susceptibility to infection is unknown.
Objectives: To ascertain the role of the 4G/5G polymorphism and other genetic variants within the PAI-1 gene. We hypothesized that variants associated with increased PAI-1 expression would be associated with an increased occurrence of community-acquired pneumonia (CAP).
Methods: Longitudinal analysis (>12 yr) of the Health, Aging, and Body Composition cohort, aged 65–74 years at start of analysis.
Measurements and Main Results: We genotyped the 4G/5G PAI-1 polymorphism and six additional single nucleotide polymorphisms. Of the 3,075 subjects, 272 (8.8%) had at least one hospitalization for CAP. Among whites, variants at the PAI4G,5G, PAI2846, and PAI7343 sites had higher risk of CAP (P = 0.018, 0.021, and 0.021, respectively). At these sites, variants associated with higher PAI-1 expression were associated with increased CAP susceptibility. Compared with the 5G/5G genotypes at PAI4G,5G site, the 4G/4G and 4G/5G genotypes were associated with a 1.98-fold increased risk of CAP (95% confidence interval, 1.2–3.2; P = 0.006). In whole blood stimulation assay, subjects with a 4G allele had 3.3- and 1.9-fold increased PAI-1 expression (P = 0.043 and 0.034, respectively). In haplotype analysis, the 4G/G/C/A haplotype at the PAI4G,5G, PAI2846, PAI4588, and PAI7343 single nucleotide polymorphisms was associated with higher CAP susceptibility, whereas the 5G/G/C/A haplotype was associated with lower CAP susceptibility. No associations were seen among blacks.
Conclusions: Genotypes associated with increased expression of PAI-1 were associated with increased susceptibility to CAP in elderly whites.
doi:10.1164/rccm.200605-644OC
PMCID: PMC2176102  PMID: 17761618
pneumonia; inflammatory markers; PAI-1; gene; haplotype
9.  Informal Caregiver Burden among Survivors of Prolonged Mechanical Ventilation 
Rationale: Although caregiver burden is well described in chronic illness, few studies have examined burden among caregivers of survivors of critical illness. In existing studies, it is unclear whether the observed burden is a consequence of critical illness or of preexisting patient illness.
Objectives: To describe 1-yr longitudinal outcomes for caregivers of patients who survived critical illness, and to compare depression risk between caregivers of patients with and without pre–intensive care unit (ICU) functional dependency.
Methods: Prospective, parallel, cohort study of survivors of prolonged (greater than 48 h) mechanical ventilation and their informal caregivers. Caregivers were divided into two cohorts on the basis of whether patients were functionally independent (n = 99, 59%), or dependent (n = 70, 41%) before admission. Functional dependency was defined as dependency in one or more activities of daily living or in three or more instrumental activities of daily living. Patient and caregiver outcomes were measured 2, 6, and 12 mo after mechanical ventilation initiation.
Measurements and Main Results: We studied three caregiver outcomes: depression risk, lifestyle disruption, and employment reduction. Most patients were male (59.8%), with a mean (SD) age of 56.6 (19.0) yr. Caregivers were mostly female (75.7%), with a mean (SD) age of 54.6 (14.7) yr. Prevalence of caregiver depression risk was high at all time points (33.9, 30.8, and 22.8%; p = 0.83) and did not vary by patient pre-ICU functional status. Lifestyle disruption and employment reduction were also common and persistent.
Conclusions: Depression symptoms, lifestyle disruption, and employment reduction were common among informal caregivers of critical illness survivors. Depression risk was high regardless of patient pre-ICU functional status.
doi:10.1164/rccm.200604-493OC
PMCID: PMC1899280  PMID: 17068327
caregivers; depression; mechanical ventilation; outcomes research; quality of life

Results 1-9 (9)