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Background: Matrix Metalloproteinases (MMP) respond to tissue damage during sepsis. Higher plasma concentrations of MMPs and the tissue-inhibitor of matrix metalloproteinases (TIMP) have been reported in sepsis compared with healthy controls. The objective of this study was to examine if plasma levels of MMP-3, MMP-9, and TIMP-1 associate with mortality and organ dysfunction during sepsis. Methods: We conducted a prospective cohort study of critically ill patients with sepsis adjudicated per Sepsis-3 criteria at a tertiary academic medical center. We measured plasma concentrations of MMP-3, MMP-9, and TIMP-1 on intensive care unit admission. We phenotyped the subjects for shock, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality at 30 days. We used logistic regression to test the associations between the MMPs and TIMP-1 with shock, ARDS, AKI, and mortality. Results: Higher plasma TIMP-1 levels were associated with shock (odds ratio [OR] 1.51 per log increase [95% CI 1.25, 1.83]), ARDS (OR 1.24 [95% CI 1.05, 1.46]), AKI (OR 1.18 [95% CI 1.01, 1.38]), and mortality (OR 1.20 [95% CI 1.05, 1.46]. Higher plasma MMP-3 concentrations were associated with shock (OR 1.40 [95% CI 1.12, 1.75]) and mortality (OR 1.24 [95% CI 1.03, 1.48]) whereas MMP-9 levels were not associated with outcomes. Higher plasma TIMP-1 to MMP-3 ratios were associated with shock (OR 1.41 [95% CI 1.15, 1.72], P = 0.02). Conclusion: Elevated plasma concentrations of TIMP-1 associate with organ dysfunction and mortality in sepsis. Higher plasma levels of MMP-3 associate with shock and mortality. Plasma MMP and TIMP-1 may warrant further investigation as emerging sepsis theragnostic biomarkers.

In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units., Visual Abstract. COVID-19–Related Critical Illness In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units. Visual Abstract. COVID-19–Related Critical Illness In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units., 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. Limitation: 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 Coronavirus Disease 2019 (COVID-19) has caused over 1 200 000 deaths worldwide as of November 2020. However, little is known about the clinical outcomes among hospitalized patients with active COVID-19 after in-hospital cardiac arrest (IHCA). Aim We aimed to characterize outcomes from IHCA in patients with COVID-19 and to identify patient- and hospital-level variables associated with 30-day survival. Methods We conducted a multicentre retrospective cohort study across 11 academic medical centres in the U.S. Adult patients who received cardiopulmonary resuscitation and/or defibrillation for IHCA between March 1, 2020 and May 31, 2020 who had a documented positive test for Severe Acute Respiratory Syndrome Coronavirus 2 were included. The primary outcome was 30-day survival after IHCA. Results There were 260 IHCAs among COVID-19 patients during the study period. The median age was 69 years (interquartile range 60–77), 71.5% were male, 49.6% were White, 16.9% were Black, and 16.2% were Hispanic. The most common presenting rhythms were pulseless electrical activity (45.0%) and asystole (44.6%). ROSC occurred in 58 patients (22.3%), 31 (11.9%) survived to hospital discharge, and 32 (12.3%) survived to 30 days. Rates of ROSC and 30-day survival in the two hospitals with the highest volume of IHCA over the study period compared to the remaining hospitals were considerably lower (10.8% vs. 64.3% and 5.9% vs. 35.7% respectively, p Conclusions We found rates of ROSC and 30-day survival of 22.3% and 12.3% respectively. There were large variations in centre-level outcomes, which may explain the poor survival in prior studies.

Background With rising obesity rates in the United States, knowledge of obesity's impact on trauma outcomes is essential to providing high-quality care. The interaction between body mass and outcomes is unclear, with existing literature demonstrating conflicting results. We hypothesized that in a broad cohort of trauma patients, obesity would be associated with in-hospital mortality. Materials and methods We conducted a retrospective cohort study using the 2014-2015 Pennsylvania Trauma Outcomes Study (PTOS) registry, a state-wide registry to which all accredited Pennsylvania trauma centers are required to report. We included nonburn adult trauma patients admitted to level I and II centers. Because PTOS lacks height data, weight thresholds of 111.75 kg for men and 95.05 kg for women were used, which correspond to BMI = 30 kg/m2 at the 99th height percentile in the United States. We tested the association of obesity with in-hospital mortality using logistic regression to adjust for confounders. Results We included 46,329 patients in a complete case analysis. In univariate logistic regression analysis, injury mechanism, presence of a complication, age, sex, need for blood transfusion, Revised Trauma Score, and Injury Severity Score were associated with mortality. On multivariate analysis, including these factors, obesity was significantly associated with mortality (odds ratio 1.36, 95% confidence interval 1.10-1.69). Respiratory, thromboembolic, and infectious complications, as defined by PTOS, were more common in obese patients. Conclusions After adjusting for patient and injury characteristics, obesity is associated with increased mortality following trauma. This information may help resolve previous conflicting evidence and guide providers in caring for the obese patient.

Supplemental Digital Content is available in the text., BACKGROUND: The U.S. Food and Drug Administration has to date granted approval or emergency use authorization to three vaccines against severe acute respiratory syndrome coronavirus 2 and coronavirus disease 2019. In clinical trials and real-use observational studies, the Pfizer-BioNTech BNT162b2 messenger RNA coronavirus disease 2019 vaccine, as well as the Moderna mRNA-1273 messenger RNA coronavirus disease 2019 vaccine, have demonstrated high efficacy and few adverse events. CASE SUMMARY: A 20-year-old male college student in good health developed tinnitus and hematuria shortly after vaccination and progressed swiftly to a syndrome of: systemic inflammation; acute kidney injury requiring hemodialysis; acute, bilateral, complete sensorineural hearing loss; radiographic evidence of acute multifocal ischemic strokes; pericardial effusion complicated by tamponade physiology requiring pericardial evacuation; pleural effusions requiring evacuation; and systemic capillary leak. An extensive clinical and research investigation, including cytokine analysis, whole blood cytometry by time of flight, and whole exome sequencing, did not reveal a definitive explanatory mechanism. CONCLUSION: While the overall safety profile of the BNT162b2 coronavirus disease 2019 vaccine remains excellent for the general population, rare serious events have been reported. In this report, we describe a case of multisystem inflammation and organ dysfunction of unknown mechanism beginning shortly after administration of the first dose of BNT162b2 coronavirus disease 2019 vaccine in a previously healthy recipient.

Summary: Background: Acute respiratory distress syndrome (ARDS) is a common, but under-recognised, critical illness syndrome associated with high mortality. An important factor in its under-recognition is the variability in chest radiograph interpretation for ARDS. We sought to train a deep convolutional neural network (CNN) to detect ARDS findings on chest radiographs. Methods: CNNs were pretrained on 595 506 radiographs from two centres to identify common chest findings (eg, opacity and effusion), and then trained on 8072 radiographs annotated for ARDS by multiple physicians using various transfer learning approaches. The best performing CNN was tested on chest radiographs in an internal and external cohort, including a subset reviewed by six physicians, including a chest radiologist and physicians trained in intensive care medicine. Chest radiograph data were acquired from four US hospitals. Findings: In an internal test set of 1560 chest radiographs from 455 patients with acute hypoxaemic respiratory failure, a CNN could detect ARDS with an area under the receiver operator characteristics curve (AUROC) of 0·92 (95% CI 0·89–0·94). In the subgroup of 413 images reviewed by at least six physicians, its AUROC was 0·93 (95% CI 0·88–0·96), sensitivity 83·0% (95% CI 74·0–91·1), and specificity 88·3% (95% CI 83·1–92·8). Among images with zero of six ARDS annotations (n=155), the median CNN probability was 11%, with six (4%) assigned a probability above 50%. Among images with six of six ARDS annotations (n=27), the median CNN probability was 91%, with two (7%) assigned a probability below 50%. In an external cohort of 958 chest radiographs from 431 patients with sepsis, the AUROC was 0·88 (95% CI 0·85–0·91). When radiographs annotated as equivocal were excluded, the AUROC was 0·93 (0·92–0·95). Interpretation: A CNN can be trained to achieve expert physician-level performance in ARDS detection on chest radiographs. Further research is needed to evaluate the use of these algorithms to support real-time identification of ARDS patients to ensure fidelity with evidence-based care or to support ongoing ARDS research. Funding: National Institutes of Health, Department of Defense, and Department of Veterans Affairs.

Rationale: Exposure to air pollution has molecular and physiologic effects on the lung that may increase the risk of acute respiratory distress syndrome (ARDS) after injury. Objectives: To determine the association of short- and long-term air pollutant exposures and ARDS risk after severe trauma. Methods: We analyzed data from a prospective cohort of 996 critically ill patients presenting with acute trauma and an injury severity score greater than 15. Exposures to ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and particulate matter less than 2.5 μm were assessed by weighted averages of daily levels from all monitors within 50 km of the geocoded location of a patient’s residence. Patients were followed for 6 days for the development of ARDS according to Berlin Criteria. The association between each exposure and ARDS was determined via multivariable logistic regression adjusting for potential confounders. Measurements and Main Results: ARDS developed in 243 (24%) patients. None of the short-term exposures averaged over the 3 days before presentation was associated with ARDS, except sulfur dioxide, which demonstrated a nonlinear association. Nitrogen dioxide, sulfur dioxide, and particulate matter less than or equal to 2.5 μm in aerodynamic diameter exposure over the 6 weeks before presentation was significantly associated with ARDS (P

Rationale: Respiratory viruses are commonly detected pathogens in pulmonary sepsis. Prior studies have demonstrated that patients with respiratory viral infections may have transient lymphocytopenia and thrombocytopenia. Leukocyte parameters including lymphocyte to monocyte ratio (LMR) and neutrophil to lymphocyte ratio (NLR) have been reported as screening tools for viral infections. Platelet counts and dynamics have been described as quantitative traits for ARDS risk and mortality. Therefore, we hypothesized that early hematologic parameters including lymphocyte count, monocyte count, platelet count, NLR, and LMR may distinguish viral from bacterial pulmonary sepsis. Methods: We enrolled 1,158 critically ill patients with pulmonary sepsis from 2009 to 2020 and measured lymphocyte count, monocyte count, platelet count, NLR, and LMR on ICU admission and at 24-hrs. Respiratory viruses were detected via PCR panel on nasopharyngeal swabs. Pulmonary sepsis was adjudicated by a physician panel. APACHE III scores were collected during the first 24-hrs. Shock was assessed by vasopressor use or mean arterial pressure

The prevalence of obesity is rising worldwide. Adipose tissue exerts anatomic and physiologic effects with significant implications for critical illness. Changes in respiratory mechanics cause expiratory flow limitation, atelectasis, and ventilation/perfusion mismatch with resultant hypoxemia. Altered work of breathing and obesity hypoventilation syndrome may cause hypercapnia. Challenging mask ventilation and peri-intubation hypoxemia may complicate intubation. Patients with obesity are at increased risk of acute respiratory distress syndrome and should receive lung-protective ventilation based on predicted body weight. Increased positive end expiratory pressure (PEEP), coupled with appropriate patient positioning, may overcome the alveolar decruitment and intrinsic PEEP caused by elevated baseline pleural pressure, though evidence is insufficient regarding the impact of high PEEP strategies on outcomes. Venovenous extracorporeal membrane oxygenation may be safely performed in patients with obesity. Fluid management should account for increased prevalence of chronic heart and kidney disease, expanded blood volume, and elevated acute kidney injury risk. Medication pharmacodynamics and pharmacokinetics may be altered by hydrophobic drug distribution to adipose depots and comorbid liver or kidney disease. Obesity is associated with increased risk of venous thromboembolism and infection; appropriate dosing of prophylactic anti-coagulation and early removal of indwelling catheters may decrease these risks. Obesity is associated with improved critical illness survival in some studies. It is unclear whether this reflects a protective effect or limitations inherent to observational research. Obesity is associated with increased risk of intubation and death in SARS-CoV-2 infection. Ongoing molecular studies of adipose tissue may deepen understanding of how obesity impacts critical illness pathophysiology.

Background: Management of patients with acute deterioration from novel coronavirus disease of 2019 (COVID-19) has posed a particular challenge for rapid response systems (RRSs) due to increased hospital strain and direct risk of infection to RRS team members. Objective: We sought to characterize RRS structure and protocols adaptions during the COVID-19 pandemic. Design, setting, and participants: Internet-based cross-sectional survey of RRS leaders, physicians, and researchers across the United States. Results: Clinicians from 46 hospitals were surveyed, 40 completed a baseline survey (87%), and 19 also completed a follow-up qualitative survey. Most reported an increase in emergency team resources during the COVID-19 pandemic. The number of sites performing simulation training sessions decreased from 88% before COVID-19 to 53% during the pandemic. Conclusions: Most RRSs reported pandemic-related adjustments, most commonly through increasing resources and implementation of protocol changes. There was a reduction in the number of sites that performed simulation training.

BACKGROUND: The ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases, including acute respiratory distress syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation. METHODS: We conducted analyses in 3 cohorts of critically ill trauma and sepsis patients (n = 3710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined whether associations were present in FUT2-defined nonsecretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested whether blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP). RESULTS: The A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all 3 populations. In sepsis, this relationship was strongest in nonpulmonary infections. The association persisted in nonsecretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP. CONCLUSION: We identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill, possibly mediated through microvascular dysfunction and coagulation. FUNDING: NIH HL122075, HL125723, HL137006, HL137915, DK097307, HL115354, HL101779, and the University of Pennsylvania McCabe Fund Fellowship Award.

Background: Out-of-hospital cardiac arrest (OHCA) remains a leading cause of death in the US, affecting over 400,000 annually. Although outcomes have improved, rates of return of spontaneous circulation (ROSC) and survival are lower from OHCA than from in-hospital cardiac arrest. Clinical emergencies, including OHCA, in outpatient clinical settings are often first attended by rapid response teams (RRT), but the causes and outcomes from OHCA in these environments has not been characterized. An understanding of this population is critical both for RRT quality improvement and resource allocation. Objectives: We aimed to describe OHCA that occurred in outpatient clinical environments. We hypothesized that OHCA in ambulatory settings would be uncommon and would be concentrated in a limited number of higher-risk outpatient areas. Methods: Retrospective analysis of all RRT calls for non-hospitalized adult outpatients occurring between 2012- 2020 at the Hospital of the University of Pennsylvania. Results: There were 7336 RRT calls;25 were for OHCA. Information was available for 24 of these. Mean age was 64 +/- 16.7 y, and 38% were female. Initial rhythm was pulseless electrical activity in 79%, ventricular fibrillation in 13%, asystole in 4%, and was not recorded in 4%. CPR was initiated in all cases prior to the arrival of the RRT. ROSC was obtained in 84%, extracorporeal membrane oxygenation (ECMO) was initiated in 8%, and 8% did not survive. ROSC was obtained within 5 min in 58% of cases. Of those that attained ROSC, 75% survived to discharge, 80% with good neurological status (CPC 1-2). Most events (54%) were judged to be iatrogenic. Of these, 54% were due to anaphylaxis, 15% were during cardiac stress testing, and 31% were peri-procedural. The most common causes of anaphylaxis were chemotherapeutics and radiographic contrast agents. Conclusions: OHCA events are uncommon in the outpatient clinical setting and are frequently iatrogenic. These events are associated with high rates of ROSC and neurologically intact survival. Iatrogenic OHCA occurred during a limited number of clinical settings, including outpatient procedural, , infusion, and stress test locations.. This finding suggests the need to focus resuscitation training in these specific environments.

Background Nonsteroidal anti-inflammatory drugs (NSAIDS) are increasingly important alternatives to opioids for analgesia during hospitalization as health systems implement opioid-minimization initiatives. Increasing NSAID use may increase AKI rates, particularly in patients with predisposing risk factors. Inconclusive data in outpatient populations suggests that NSAID nephrotoxicity is magnified by renin-angiotensin system inhibitors (RAS-I). No studies have tested this in hospitalized patients. Methods Retrospective, active-comparator cohort study of patients admitted to four hospitals in Philadelphia, Pennsylvania. To minimize confounding by indication, NSAIDs were compared to oxycodone, and RAS-I were compared to amlodipine. We tested synergistic NSAID+RAS-I nephrotoxicity by comparing the difference in AKI rate between NSAID versus oxycodone in patients treated with RAS-I to the difference in AKI rate between NSAID versus oxycodone in patients treated with amlodipine. In a secondary analysis, we restricted the cohort to patients with baseline diuretic treatment. AKI rates were adjusted for 71 baseline characteristics with inverse probability of treatment-weighted Poisson regression. Results The analysis included 25,571 patients who received a median of 2.4 days of analgesia. The overall AKI rate was 23.6 per 1000 days. The rate difference (RD) for NSAID versus oxycodone in patients treated with amlodipine was 4.1 per 1000 days (95% CI, −2.8 to 11.1), and the rate difference for NSAID versus oxycodone in patients treated with RAS-I was 5.9 per 1000 days (95% CI, 1.9 to 10.1), resulting in a nonsignificant interaction estimate: 1.85 excess AKI events per 1000 days (95% CI, −6.23 to 9.92). Analysis in patients treated with diuretics produced a higher, albeit nonsignificant, interaction estimate: 9.89 excess AKI events per 1000 days (95% CI, −5.04 to 24.83). Conclusions Synergistic nephrotoxicity was not observed with short-term NSAID+RAS-I treatment in the absence of concomitant diuretics, suggesting that RAS-I treatment may not be a reason to choose opioids in lieu of NSAIDs in this population. Synergistic nephrotoxicity cannot be ruled out in patients treated with diuretics.

Objective The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis. Research Design and Methods A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity. Results ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis. Conclusions For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.

Purpose The objective of this study is to describe the relationship between two quantitative muscle ultrasound measures, the rectus femoris cross-sectional area (RF-CSA) and quadriceps muscle thickness, with volitional measures of strength and function in critically ill patients with sepsis. Materials and methods We performed a prospective study of patients admitted to a medical ICU with sepsis and shock or respiratory failure. We examined the association of two ultrasound measurements – the RF-CSA and quadriceps muscle thickness – with strength and function at day 7. Strength was determined using the Medical Research Council Score and function using Physical Function in the ICU Test, scored. Results Twenty-nine patients were enrolled; 19 patients had outcome testing performed. Over 7 days, RF-CSA and thickness decreased by an average of 23.2% and 17.9%, respectively. The rate of change per day of RF-CSA displayed a moderate correlation with strength (ρ 0.51, p-value 0.03) on day 7. Baseline and day 7 RF-CSA did not show a significant correlation with either outcome. Quadriceps muscle thickness did not significantly correlate with either outcome. Conclusions Muscle atrophy as detected by the rate of change in RF-CSA moderately correlated with strength one week after sepsis admission.

Amiodarone inhibits warfarin metabolism and is associated with major bleeding during warfarin therapy. Managing this drug-drug interaction (DDI) is challenging because of substantial interpatient variability in DDI magnitude. Because renal dysfunction induces changes in drug metabolism and protein binding that could alter cytochrome P450 inhibition mechanisms, we hypothesized that renal dysfunction alters the impact of the warfarin-amiodarone DDI. We tested this question in a propensity-matched cohort study of hospitalized patients with atrial fibrillation. Patients were queried from an electronic health record database. Renal function was estimated with creatinine clearance (CrCl). Warfarin response was measured with the warfarin sensitivity index (WSI), a dose-normalized international normalized ratio (INR) measure, and was modeled with multilevel mixed-effects linear regression. Time to supratherapeutic INR (> 4) was modeled using Cox regression. Propensity score matching resulted in 4,518 patients administered amiodarone and 4,518 controls. Amiodarone's effect on warfarin response varied threefold across the renal function range, increasing WSI by 36% in patients with normal renal function (CrCl 115 mL/minute), but by only 11.8% in patients with severe renal dysfunction (CrCl 15 mL/minute). Similarly, amiodarone had a strong effect in patients with normal renal function (hazard ratio (HR) 1.80; 1.23, 2.64), but a negligible effect on supratherapeutic INR hazard in patients with severe renal dysfunction (HR 1.01; 0.75, 1.37). These results suggest that renal function is a novel factor that explains substantial variability in the warfarin-amiodarone DDI. This information could inform warfarin dosage adjustment and monitoring and may have implications for the selection of oral anticoagulation agents in patients treated with amiodarone.

Background Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors. Methods In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies. Measurements and main results An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor. Conclusions Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

Purpose Priority on waitlist urgency over post-transplant survival has decreased waitlist mortality with no appreciable change in short to mid-term survival. We sought to define the effects of increased pressure to transplant sicker candidates on PGD incidence and mortality as a leading indicator for long-term effects. Methods We used the multi-center prospective Lung Transplant Outcomes Group cohort study, designed to identify risk factors for PGD and mortality. Patients were enrolled from August 2011 to June 2018 at 10 centers. PGD was graded based on the 2016 PGD consensus ISHLT guidelines. Specifically, PGD was defined as grade 3 PGD (PaO2 /FiO2 ratio Results 1,528 subjects were enrolled with a 25.6% incidence of PGD overall. PGD incidence increased from 14.3% to 38.2% over the course of the study. From 2012 to 2018, the median LAS increased from 38.7 to 42.9 and the use of ECMO salvage increased from 5.7% to 20.9% (Fig.1a). PGD was associated with mortality overall (p=0.0001, Fig.1b). Bridging strategies were not associated with mortality (p=0.66); however, salvage ECMO for PGD was significantly associated with mortality (HR 2.1 [1.6; 2.8]; p Conclusion Severity of illness continues to rise in modern surgical practice paralleled by significant increases in PGD incidence. Bridging strategies have increased but appear safe. PGD is highly associated with mortality and is increasingly treated with salvage ECMO. Though early mortality associated with salvage strategies is low, 1-year survival is significantly reduced. Given the increase in use of salvage ECMO, further work is needed on evaluating 2016 PGD definition.

Purpose Studies have shown in solid organ transplantation that multiple listing is advantageous. We therefore performed this study to determine if disparities in multiple listing exist and if differences in LAS between multiple listed (ML) and single listed (SL) candidates affect transplantation and survival rates. Methods We conducted a retrospective cohort study utilizing de-identified data provided by the OPTN's Standard Transplant Analysis and Research files. Subjects in this study consisted of adult patients listed between 2005 and 2018 for lung transplant, excluding multi-visceral and repeat lung transplants. Multiple listing was defined as registration at two or more transplant centers, where the subsequent listings occurred within 750 days of the first listing. Results 30,879 subjects were included in the final analysis, 7.61% of whom were determined to be ML candidates. Mean LAS for ML was lower at initial listing (Fig 1a). Female gender, white race, cystic fibrosis diagnosis, higher level of education, and private insurance were each independently associated with multiple listing (Fig 1a). Despite multiple listing, ML candidates were less likely to be transplanted (OR 0.22 [0.20, 0.25], p=0.001). SL candidates displayed quicker transplantation rates at 90, 180, and 365 days from initial listing (log rank p Conclusion ML groups have significantly different demographics than SL groups. ML groups appear to have higher education, are younger, and are less likely to be underrepresented minorities. Lower LAS was also noted in ML candidates which may explain why they wait longer. Further investigation of disparities in access to transplant and multiple listing is further warranted.

Aim: Determine changes in rapid response team (RRT) activations and describe institutional adaptations made during a surge in hospitalizations for coronavirus disease 2019 (COVID-19). Methods: Using prospectively collected data, we compared characteristics of RRT calls at our academic hospital from March 7 through May 31, 2020 (COVID-19 era) versus those from January 1 through March 6, 2020 (pre-COVID-19 era). We used negative binomial regression to test differences in RRT activation rates normalized to floor (non-ICU) inpatient census between pre-COVID-19 and COVID-19 eras, including the sub-era of rapid COVID-19 census surge and plateau (March 28 through May 2, 2020). Results: RRT activations for respiratory distress rose substantially during the rapid COVID-19 surge and plateau (2.38 (95% CI 1.39–3.36) activations per 1000 floor patient-days v. 1.27 (0.82–1.71) during the pre-COVID-19 era; p = 0.02); all-cause RRT rates were not significantly different (5.40 (95% CI 3.94–6.85) v. 4.83 (3.86–5.80) activations per 1000 floor patient-days, respectively; p = 0.52). Throughout the COVID-19 era, respiratory distress accounted for a higher percentage of RRT activations in COVID-19 versus non-COVID-19 patients (57% vs. 28%, respectively; p = 0.001). During the surge, we adapted RRT guidelines to reduce in-room personnel and standardize personal protective equipment based on COVID-19 status and risk to providers, created decision-support pathways for respiratory emergencies that accounted for COVID-19 status uncertainty, and expanded critical care consultative support to floor teams. Conclusion: Increased frequency and complexity of RRT activations for respiratory distress during the COVID-19 surge prompted the creation of clinical tools and strategies that could be applied to other hospitals.

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 12.5 μ g/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.

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.

Rationale: Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptor for advanced glycation end products) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown. Objectives: Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian randomization (MR), a statistical method to infer causality using observational data. Methods: We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole-genome genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations (P 0.02). We applied the inverse variance–weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk. Measurements and Main Results: There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (odds ratio, 1.86; 95% confidence interval [1.54–2.25]; 2.56 [2.14–3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a β estimate of 0.50 (95% confidence interval [0.09–0.91] per log increase). Conclusions: Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk, suggesting plasma sRAGE acts as a causal intermediate in sepsis-related ARDS.

Background Necroptosis, a form of programmed cell death mediated by receptor interacting serine/threonine-protein kinase-3 (RIPK3), is implicated in murine models of acute respiratory distress syndrome (ARDS). We hypothesized that plasma RIPK3 concentrations in sepsis and trauma would be associated with ARDS development and that plasma RIPK3 would reflect changes in lung tissue RIPK3 in a murine model of systemic inflammation. Methods We utilized prospective cohort studies of critically ill sepsis (n = 120) and trauma (n = 180) patients and measured plasma RIPK3 at presentation and 48 h. Patients were followed for 6 days for ARDS by the Berlin definition. We used multivariable logistic regression to determine the association of plasma RIPK3 with ARDS in each cohort, adjusting for confounders. In mice, we determined whether plasma and lung tissue RIPK3 levels rise concomitantly 4 h after injection with lipopolysaccharide and ZVAD-FMK, an apoptosis inhibitor. Results The change in plasma RIPK3 from presentation to 48 h (ΔRIPK3) was associated with ARDS in sepsis (OR 1.30, 95% CI 1.03–1.63, per ½ standard deviation) and trauma (OR 1.79, 95% CI 1.33–2.40). This association was not evident for presentation RIPK3 levels. Secondary analyses showed similar findings for the association of ΔRIPK3 with acute kidney injury and 30-day mortality. Mice injected with lipopolysaccharide and ZVAD-FMK had significantly higher plasma (p

Background Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality. Methods We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders. Results Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality. Conclusions Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD.

Background Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis. Methods Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population. Results ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/μL; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/μL; 95% CI, 1.12-2.06 [P = .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/μL; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/μL; 95% CI, 0.68-1.59 [P = .84], n = 51; P = .014 for interaction). Conclusions Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS.

Purpose Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies highlight the role of donor smoking in poor post-transplant outcomes. We therefore aimed to identify clinical risk factors for PGD after lung transplantation, more accurately assess the impact of donor smoking, and develop an accurate, generalizable PGD prediction model. Methods We performed a 10-center prospective cohort study of patients in the Lung Transplant Outcomes Group from 2012-2018. PGD was defined as grade 3 PGD at 48 or 72 hours after lung reperfusion. We defined donor smoking history by clinical documentation, UNOS-reported donor smoking, or donor cotinine >9 mg/ml from urine collected at organ procurement. Building on our prior PGD prediction models, multivariable logistic regression was used to identify PGD risk factors and develop regularized predictive models with a simple user interface (R shiny). Results Of 1180 patients, 26% developed PGD and 633 (53%) received an organ from a previously smoking donor. The PGD predictive model included novel predictors of center and donor distance plus recipient age, lung allocation score (LAS), body mass index, pulmonary artery pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor distance; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The predictive model offers decision making benefit in the PGD risk range of 0.15-0.5. Donor smoking was associated with increased risk of PGD but not patient mortality (Figure 1). Conclusion We developed a clinically applicable PGD predictive algorithm based on modern lung transplant practices to aid in transplant decision making, post-transplant care, and to facilitate development of enriched PGD treatment trials. Donor smoking is a risk factor for PGD development but is not associated with increased mortality, potentially because of a lower risk phenotype of PGD occurring in smoking donor recipients.

IMPACT: This work identifies host immune perturbations in sepsis mortality that suggests targets for a precision medicine paradigm in the host response to infection. OBJECTIVES/GOALS: To compare the early whole blood transcriptome during sepsis between 30-day survivors and non-survivors in the Intensive Care Unit (ICU), and to evaluate for pathway enrichment that might explain sepsis lethality. METHODS/STUDY POPULATION: We enrolled 162 sepsis patients in the first 24 hours of ICU admission, particularly targeting individuals requiring vasopressors. Peripheral whole blood was collected in PAXgene vacutainers. Isolated RNA was analyzed with Affymetrix Human Genome ST 2.0 microarray. Differential gene expression was performed with Bioconductor/R/limma using log2 fold-change +/-0.6 as a threshold for differential expression, and a Benjamini-Hochberg adjusted p-value

Acute kidney injury (AKI) is common after lung transplantation, but molecular markers remain poorly studied. The endothelial activation markers soluble thrombomodulin (sTM), protein C, and plasminogen activator inhibitor-1 (PAI-1) are implicated in kidney microcirculatory injury in animal models of AKI. We tested the association of 6-hour postreperfusion plasma levels of these markers with posttransplant AKI severity in patients enrolled in the Lung Transplant Outcomes Group prospective cohort study at the University of Pennsylvania during two eras: 2004-06 (n = 61) and 2013-15 (n = 67). We defined AKI stage through postoperative day 5 using Kidney Disease Improving Global Outcomes creatinine criteria. We used multivariable ordinal logistic regression to determine the association of each biomarker with AKI, adjusted for primary graft dysfunction and extracorporeal life support. AKI occurred in 57 (45%) patients across both eras: 28 (22%) stage 1, 29 (23%) stage 2-3. Higher sTM and lower protein C plasma levels were associated with AKI stage in each era and remained so in multivariable models utilizing both eras (sTM: OR 1.76 [95% CI 1.19-2.60] per standard deviation, P = .005; protein C: OR 0.54 [1.19-2.60], P = .003). We conclude that 6-hour postreperfusion plasma sTM and protein C levels are associated with early postlung transplant AKI severity.

Background and objective ABO blood types are determined by antigen modifications on glycoproteins and glycolipids and associated with altered plasma levels of inflammatory and endothelial injury markers implicated in AKI pathogenesis. We sought to determine the association of ABO blood types with AKI risk in critically ill patients with trauma or sepsis. Design, setting, participants, & measurements We conducted two prospective cohort studies at an urban, academic, level I trauma center and tertiary referral center; 497 patients with trauma admitted to the surgical intensive care unit between 2005 and 2010 with an injury severity score >15 and 759 patients with severe sepsis admitted to the medical intensive care unit between 2008 and 2013 were followed for 6 days for the development of incident AKI. AKI was defined by Acute Kidney Injury Network creatinine and dialysis criteria. Results Of 497 patients with trauma, 134 developed AKI (27%). In multivariable analysis, blood type A was associated with higher AKI risk relative to type O among patients of European descent (n=229; adjusted risk, 0.28 versus 0.14; risk difference, 0.14; 95% confidence interval, 0.03 to 0.24; P=0.02). Of 759 patients with sepsis, AKI developed in 326 (43%). Blood type A again conferred higher AKI risk relative to type O among patients of European descent (n=437; adjusted risk, 0.53 versus 0.40; risk difference, 0.14; 95% confidence interval, 0.04 to 0.23; P=0.01). Findings were similar when analysis was restricted to those patients who did not develop acute respiratory distress syndrome or were not transfused. We did not detect a significant association between blood type and AKI risk among individuals of African descent in either cohort. Conclusions Blood type A is independently associated with AKI risk in critically ill patients with trauma or severe sepsis of European descent, suggesting a role for ABO glycans in AKI susceptibility.

Background and objectives Use of small changes in serum creatinine to diagnose AKI allows for earlier detection but may increase diagnostic false–positive rates because of inherent laboratory and biologic variabilities of creatinine. Design, setting, participants, & measurements We examined serum creatinine measurement characteristics in a prospective observational clinical reference cohort of 2267 adult patients with AKI by Kidney Disease Improving Global Outcomes creatinine criteria and used these data to create a simulation cohort to model AKI false–positive rates. We simulated up to seven successive blood draws on an equal population of hypothetical patients with unchanging true serum creatinine values. Error terms generated from laboratory and biologic variabilities were added to each simulated patient’s true serum creatinine value to obtain the simulated measured serum creatinine for each blood draw. We determined the proportion of patients who would be erroneously diagnosed with AKI by Kidney Disease Improving Global Outcomes creatinine criteria. Results Within the clinical cohort, 75.0% of patients received four serum creatinine draws within at least one 48-hour period during hospitalization. After four simulated creatinine measurements that accounted for laboratory variability calculated from assay characteristics and 4.4% of biologic variability determined from the clinical cohort and publicly available data, the overall false–positive rate for AKI diagnosis was 8.0% (interquartile range =7.9%–8.1%), whereas patients with true serum creatinine ≥1.5 mg/dl (representing 21% of the clinical cohort) had a false–positive AKI diagnosis rate of 30.5% (interquartile range =30.1%–30.9%) versus 2.0% (interquartile range =1.9%–2.1%) in patients with true serum creatinine values P Conclusions Use of small serum creatinine changes to diagnose AKI is limited by high false–positive rates caused by inherent variability of serum creatinine at higher baseline values, potentially misclassifying patients with CKD in AKI studies.

Objective Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration. Design Retrospective subgroup analysis of randomized controlled trial. Setting Multicenter North American and European clinical trial. Patients Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population. Interventions Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours. Measurements and main results We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant. Conclusions We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.

Background: Acute kidney injury is common in hospitalized patients, increases morbidity and mortality, and is under-recognized. To improve provider recognition, we previously developed an electronic alert system for acute kidney injury. To test the hypothesis that this electronic acute kidney injury alert could improve patient outcome, we designed a randomized controlled trial to test the effectiveness of this alert in hospitalized patients. The study design presented several methodologic, ethical, and statistical challenges. Purpose: To highlight the challenges faced and the solutions employed in the design and implementation of a clinical trial to determine whether the provision of an early electronic alert for acute kidney injury would improve outcomes in hospitalized patients. Challenges included how to randomize the delivery of the alert system and the ethical framework for waiving informed consent. Other methodologic challenges included the selection and statistical evaluation of our study outcome, a ranked-composite of a continuous covariate (creatinine) and two dichotomous outcomes (dialysis and death), and the use of the medical record as a source of trial data. Methods: We have designed a randomized trial to assess the effectiveness of an electronic alert system for acute kidney injury. With broad inclusion criteria, and a waiver of informed consent, we enroll and randomize virtually every patient with acute kidney injury in our hospital. Results: As of 31 March 2014, we have enrolled 2373 patients of 2400 targeted. Pre-alert data demonstrated a strong association between severity of acute kidney injury and inpatient mortality with a range of 6.4% in those with mild, stage 1 acute kidney injury, to 29% among those with stage 3 acute kidney injury (p < 0.001). We judged that informed consent would undermine the scientific validity of the study and present harms that are out of proportion to the very low risk intervention. Conclusion: Our study demonstrates the feasibility of designing an ethical randomized controlled trial of an early electronic alert for acute kidney injury without obtaining informed consent from individual participants. Our study outcome may serve as a model for other studies of acute kidney injury, insofar as our paradigm accounts for the effect that early death and dialysis have on assessment of acute kidney injury severity as defined by maximum achieved serum creatinine.

Background ABO glycosyltransferases catalyze antigen modifications on various glycans and glycoproteins and determine the ABO blood types. Blood type A has been associated with increased risk of vascular diseases and differential circulating levels of proteins related to inflammation and endothelial function. The objective of this study was to determine the association of ABO blood types with ARDS risk in patients with major trauma and severe sepsis. Methods We conducted prospective cohort studies in two populations at an urban tertiary referral, level I trauma center. Critically ill patients (n = 732) presenting after major trauma were followed for 5 days for ARDS development. Additionally, 976 medical patients with severe sepsis were followed for 5 days for ARDS. Multivariable logistic regression was used to adjust for confounders. Results ARDS developed in 197 of the 732 trauma patients (27%). Blood type A was associated with increased ARDS risk among whites (37% vs 24%; adjusted OR, 1.88; 95% CI, 1.14-3.12; P = .014), but not blacks (adjusted OR, 0.61; 95% CI, 0.33-1.13; P = .114). ARDS developed in 222 of the 976 patients with severe sepsis (23%). Blood type A was also associated with an increased ARDS risk among whites (31% vs 21%; adjusted OR, 1.67; 95% CI, 1.08-2.59; P = .021) but, again, not among blacks (adjusted OR, 1.17; 95% CI, 0.59-2.33; P = .652). Conclusions Blood type A is associated with an increased risk of ARDS in white patients with major trauma and severe sepsis. These results suggest a role for ABO glycans and glycosyltransferases in ARDS susceptibility.