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Background: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally., Objective: To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery., Design: Single-health system, multihospital retrospective cohort study., Setting: 5 hospitals within the University of Pennsylvania Health System., Patients: Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic., Measurements: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions., Results: Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change., Limitations: Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications., Conclusion: Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Acute respiratory distress syndrome (ARDS) is heterogeneous and may be amenable to sub-phenotyping to improve enrichment for trials. We aimed to identify subtypes of pediatric ARDS based on whole blood transcriptomics., Methods: This was a prospective observational study of children with ARDS at the Children's Hospital of Philadelphia (CHOP) between January 2018 and June 2019. We collected blood within 24 h of ARDS onset, generated expression profiles, and performed k-means clustering to identify sub-phenotypes. We tested the association between sub-phenotypes and PICU mortality and ventilator-free days at 28 days using multivariable logistic and competing risk regression, respectively., Results: We enrolled 106 subjects, of whom 96 had usable samples. We identified three sub-phenotypes, dubbed CHOP ARDS Transcriptomic Subtypes (CATS) 1, 2, and 3. CATS-1 subjects (n = 31) demonstrated persistent hypoxemia, had ten subjects (32%) with immunocompromising conditions, and 32% mortality. CATS-2 subjects (n = 29) had more immunocompromising diagnoses (48%), rapidly resolving hypoxemia, and 24% mortality. CATS-3 subjects (n = 36) had the fewest comorbidities and also had rapidly resolving hypoxemia and 8% mortality. The CATS-3 subtype was associated with lower mortality (OR 0.18, 95% CI 0.04-0.86) and higher probability of extubation (subdistribution HR 2.39, 95% CI 1.32-4.32), relative to CATS-1 after adjustment for confounders., Conclusions: We identified three sub-phenotypes of pediatric ARDS using whole blood transcriptomics. The sub-phenotypes had divergent clinical characteristics and prognoses. Further studies should validate these findings and investigate mechanisms underlying differences between sub-phenotypes.

Introduction: Cardiac complications (CC) after injury are rare but contribute disproportionately to mortality. Variability in rates of CC and failure to rescue (FTR) after CC (FTR-C) within trauma systems may suggest opportunities for improvement, but we have not yet demonstrated the ability to identify high and low performers. We examined center-level rates of CC and FTR-C in a mature trauma system with the hypothesis that high-performing centers for each of these outcomes could be identified., Methods: Using a statewide trauma registry from 2007-2015, we developed multivariable logistic regression models on CC and FTR-C including patient demographics, physiology, comorbidity, and injury data. Predicted probabilities of each outcome were summed to generate expected event rates, which were compared to observed event rates to generate centerlevel observed-to-expected (O:E) ratios. We measured internal consistency between CC and FTR-C for centers using Cronbach's alpha., Results: Cardiac complications occurred in 5,079/278,042 (1.8%; center-level range: 0.9-3.8%) of included patients (median age 55 (IQR 34-76), 84% Caucasian, 60% male, 92% blunt, median ISS 9 (IQR5-16)). Death after CC occurred in 982/5,097 patients for an FTR-C rate of 19.3% (center-level range: 7.8-30.4%). 10/27 centers were high-performers (95% confidence interval for O:E ratio <1) for CC and 2/27 centers were high-performers for FTR-C, but internal consistency between these metrics was poor (alpha = 0.31)., Conclusion: Rates of CC and FTR-C vary significantly between hospitals in mature trauma systems but high-performing centers can be identified. Inconsistent performance between metrics suggests unknown institutional factors underlie performance for CC and FTR., (Copyright © 2020. Published by Elsevier Ltd.)

Purpose: Neuron-specific enolase (NSE) concentrations are prognostic following traumatic and anoxic brain injury and may provide a method to quantify neuronal injury in other populations. We determined the association of admission plasma NSE concentrations with mortality and delirium in critically ill septic patients., Methods: We performed a retrospective analysis of 124 patients from a larger sepsis cohort. Plasma NSE was measured in the earliest blood draw at intensive care unit admission. Primary outcomes were 30-day mortality and intensive care unit delirium determined by chart review., Results: Sixty-one patients (49.2%) died within 30 days, and delirium developed in 34 (31.5%) of the 108 patients who survived at least 24 hours and were not persistently comatose. Each doubling of the NSE concentration was associated with a 7.3% (95% confidence interval [CI] 2.5-12.0, P= .003) increased risk of 30-day mortality and a 5.2% (95% CI 3.2-7.2, P< .001) increased risk of delirium. An NSE concentration >12.5 μg/L was independently associated with a 23.3% (95% CI 6.7-39.9, P= .006) increased risk of 30-day mortality and a 29.3% (95% CI 8.8-49.8, P= .005) increased risk of delirium., Conclusions: Higher plasma NSE concentrations were associated with mortality and delirium in critically ill septic patients, suggesting that NSE may have utility as a marker of neuronal injury in sepsis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Immunocompromised patients who develop sepsis while neutropenic are at high risk for morbidity and mortality; however, it is unknown if neutropenic sepsis is associated with distinct clinical and biological characteristics., Methods: We conducted a prospective cohort study of patients admitted to the medical intensive care unit of an academic medical center with severe sepsis. Patients were followed for the development of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality. Plasma proteins, representing the host inflammatory response, anti-inflammatory response, and endothelial leak were measured in 30 % of subjects. Clinical characteristics and plasma protein concentrations of patients with neutropenia at enrollment were compared to patients without neutropenia., Results: Of 797 subjects enrolled, 103 (13 %) were neutropenic at ICU admission. The neutropenic subjects were more often in shock, admitted from the hospital ward, had higher APACHE III scores, and more likely bacteremic. Neutropenia was an independent risk factor for AKI (RR 1.28; 95 % CI 1.04, 1.57; p = 0.03), but not ARDS (RR 0.90; 95 % CI 0.70, 1.17; p = 0.42) or 30-day mortality (RR 1.05; 95 % CI 0.85, 1.31; p = 0.65). Neutropenic subjects had higher plasma interleukin (IL)-6 (457 vs. 249 pg/ml; p = 0.03), IL-8 (581 vs. 94 pg/ml; p <0.001), and granulocyte colony-stimulating factor (G-CSF) (3624 vs. 99 pg/ml; p <0.001). Angiopoietin-2 and IL-1 receptor antagonist concentrations did not differ between groups., Conclusions: Neutropenic sepsis is associated with a higher AKI risk and concentrations of inflammatory mediators IL-6, IL-8, and G-CSF relative to non-neutropenic patients. These differences may have implications for future therapies targeting neutropenic sepsis.

Background: Obesity is associated with the development of acute respiratory distress syndrome (ARDS) in at-risk patients. Low plasma levels of adiponectin, a circulating hormone-like molecule, have been implicated as a possible mechanism for this association. The objective of this study was to determine the association of plasma adiponectin level at ICU admission with ARDS and 30-day mortality in patients with severe sepsis and septic shock., Methods: This is a prospective cohort study of patients admitted to the medical ICU at the Hospital of the University of Pennsylvania. Plasma adiponectin was measured at the time of ICU admission. ARDS was defined by Berlin criteria. Multivariable logistic regression was used to determine the association of plasma adiponectin with the development of ARDS and mortality at 30 days., Results: The study included 164 patients. The incidence of ARDS within 5 days of admission was 45%. The median initial plasma adiponectin level was 7.62 mcg/ml (IQR: 3.87, 14.90) in those without ARDS compared to 8.93 mcg/ml (IQR: 4.60, 18.85) in those developing ARDS. The adjusted odds ratio for ARDS associated with each 5 mcg increase in adiponectin was 1.12 (95% CI 1.01, 1.25), p-value 0.025). A total of 82 patients (51%) of the cohort died within 30 days of ICU admission. There was a statistically significant association between adiponectin and mortality in the unadjusted model (OR 1.11, 95% CI 1.00, 1.23, p-value 0.04) that was no longer significant after adjusting for potential confounders., Conclusions: In this study, low levels of adiponectin were not associated with an increased risk of ARDS in patients with severe sepsis and septic shock. This argues against low levels of adiponectin as a mechanism explaining the association of obesity with ARDS. At present, it is unclear whether circulating adiponectin is involved in the pathogenesis of ARDS or simply represents an epiphenomenon of other unknown functions of adipose tissue or metabolic alterations in sepsis.

Background: Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis, and sepsis-associated ARDS is associated with significant morbidity and mortality. To date, no study has directly examined the epidemiology of ARDS in severe sepsis from the earliest presentation to the health care system, the emergency department (ED)., Methods: This was a single-center retrospective, observational cohort study of 778 adults with severe sepsis presenting to the ED. The primary outcome was the development of ARDS requiring mechanical ventilation during the first 5 hospital days. Acute respiratory distress syndrome was defined using the Berlin definition. We used multivariable logistic regression to identify risk factors associated independently with ARDS development., Results: The incidence of ARDS was 6.2% (48/778 patients) in the entire cohort. Acute respiratory distress syndrome development varied across the continuum of care: 0.9% of patients fulfilled criteria for ARDS in the ED, 1.4% admitted to the ward developed ARDS, and 8.9% admitted to the intensive care unit developed ARDS. Acute respiratory distress syndrome developed a median of 1 day after admission and was associated with a 4-fold higher risk of in-hospital mortality (14% vs. 60%, P < 0.001). Independent risk factors associated with increased risk of ARDS development included intermediate (2-3.9 mmol/L) (P = 0.04) and high (≥4) serum lactate levels (P = 0.008), Lung Injury Prediction score (P < 0.001), and microbiologically proven infection (P = 0.01)., Conclusions: In patients presenting to the ED with severe sepsis, the rate of sepsis-associated ARDS development varied across the continuum of care. Acute respiratory distress syndrome developed rapidly and was associated with significant mortality. Elevated serum lactate levels in the ED and a recently validated clinical prediction score were independently associated with the development of ARDS in severe sepsis.

Background: Packed red blood cell (PRBC) transfusion is associated with acute lung injury (ALI) development after trauma, but this risk may not be constant through time after trauma. We hypothesized that the relationship between PRBC delivery and ALI risk varies through time after injury., Methods: Data were collected prospectively from 1999 to 2006. Inclusion criteria include the following: older than 13 years, surgical intensive care unit admission, and Injury Severity Score of 16 or greater. Exclusion criteria included discharge/death within 24 hours of admission. Patients were followed up prospectively for ALI development for 5 days after trauma. Discrete time models were fit to test the association of timing of PRBC delivery with the development of ALI while controlling for patient demographics, resuscitation variables, Injury Severity Score, and Acute Physiology and Chronic Health Evaluation III scores., Results: At total of 602 patients were included. Median age was 33 years, 77% were male, and 50% were African American. Using a discrete time-survival model, the relation between transfusion and ALI development was found to vary by transfusion time window (p < 0.0001). The major effect of PRBC delivery on ALI risk occurred in the first 24 hours after trauma; this finding persisted in multivariable modeling (adjusted odds ratio, 1.07 per unit; 95% confidence interval, 1.02-1.11, p < 0.001). Cumulative incidence of ALI approached 50% in patients receiving 6 U of PRBC or more in the first 24 hours., Conclusion: The association between PRBC transfusion and ALI development in patients with trauma is time dependent, with PRBC delivery in the first 24 hours after injury driving the overall relation. Each PRBC unit during this period increases odds of subsequent ALI development by 7%., Level of Evidence: Prognostic/epidemiologic study, level II.