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/mu L; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/mu L; 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/mu L; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/mu L; 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.

Faust, Hilary; Wang, Yiyue; Forker, Caitlin; Dunn, Thomas; Zhang, Peggy; Lanken, Paul; Sims, Carrie; Yehya, Nadir; Christie, Jason; Meyer, Nuala; Reilly, John; Mangalmurti, Nilam; Shashaty, Michael Author Information

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 genomewide 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 0 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.

OBJECTIVES Body mass index (BMI) is associated with acute kidney injury (AKI) after trauma, but underlying mechanisms are unclear. Body mass index correlates with both excess adiposity and increased muscle mass. Since the latter could predispose to severe rhabdomyolysis after trauma, we hypothesized that the BMI-AKI association may be partially explained by a direct relationship of BMI with serum creatine kinase (CK). METHODS Prospective cohort study of 463 critically ill patients admitted to a level I trauma center from 2005 to 2015 with Injury Severity Score of >15 and serum CK measured in the first 7 days. We defined AKI by AKI Network creatinine criteria. We used simple linear regression to determine the association of BMI with peak CK and multivariable logistic regression to adjust the BMI-AKI association for peak CK and confounders. RESULTS Median age was 43 years, 350 (76%) were male, 366 (79%) had blunt mechanism, and median Injury Severity Score was 24. Body mass index was associated with peak CK ( R 2 = 0.05, p < 0.001). Acute kidney injury developed in 148 patients (32%), and median time to peak CK was 29 hours (interquartile range, 15–56 hours) after presentation. Body mass index was significantly associated with AKI in multivariable models adjusted for age, race, sex, diabetes, injury mechanism and severity, and red blood cell transfusions (odds ratio [OR], 1.31 per 5 kg/m 2 ; 95% confidence interval [CI], 1.09–1.58; p = 0.004). Adding peak CK to the model partially attenuated the association of BMI with AKI (OR, 1.26 per 5 kg/m 2 ; 95% CI, 1.04–1.52; p = 0.018), and peak CK was also associated with AKI (OR, 1.19 per natural log; 95% CI, 1.00–1.41; p = 0.049). Peak CK remained associated with AKI when restricted to patients with values of <5,000 U/L (OR, 1.31 per natural log; 95% CI, 1.01–1.69; p = 0.043). CONCLUSION Serum CK correlated with BMI and partially attenuated the association of BMI with AKI after major trauma, suggesting that excess muscle injury may contribute to the BMI-AKI association. LEVEL OF EVIDENCE Epidemiologic study, level III.

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. 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. 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 < 0.001) and lung (p = 0.005) RIPK3 than control mice. The change in plasma RIPK3 from presentation to 48 h in both sepsis and trauma patients is independently associated with ARDS, and plasma RIPK3 may reflect RIPK3 activity in lung tissue.

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 mu m 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 mm in aerodynamic diameter exposure over the 6 weeks before presentation was significantly associated with ARDS (P<0.05). All long-term exposures (3 yr) were associated with ARDS (P<0.01) in adjusted models, despite exposure levels largely below U.S. and European Union air quality standards. Conclusions: Long-term low-to moderate-level air pollutant exposure is associated with a greater risk of developing ARDS after severe trauma and represents a novel and potentially modifiable environmental risk factor for ARDS.

"Palliative Care for People with Respiratory Disease or Critical Illness." American Journal of Respiratory and Critical Care Medicine, 197(10), pp. P17–P18

Purpose Many medical schools have implemented learning communities (LCs) to improve the learning environment (LE) for students. The authors conducted this study to determine whether a relationship exists between medical student perceptions of the LE and presence of LCs during the preclerkship years. Method Students from 24 schools participating in the American Medical Association Learning Environment Study completed the 17-item Medical Student Learning Environment Survey (MSLES) at the end of their first and second years of medical school between 2011 and 2013. Mean total MSLES scores and individual item scores at the end of the first and second years in schools with and without LCs were compared with t tests, and effect sizes were calculated. Mixed-effects longitudinal models were used to control for student demographics and random school and student effects on the relationship between LC status and MSLES score. Results A total of 4,980 students (81% of 6,148 matriculants) from 18 schools with LCs and 6 without LCs participated. Mean [SD] MSLES scores were significantly higher in LC schools compared with non-LC schools at the end of year one (3.72 [0.44] versus 3.57 [0.43], P < .001) and year two (3.69 [0.49] versus 3.42 [0.54], P < .001). The effect size increased from 0.35 (small) at the end of year one to 0.53 (medium) at the end of year two. Conclusions This large multi-institutional cohort study found that LCs at medical schools were associated with more positive perceptions of the LE by preclerkship students.

DiSanto, Thomas; Reilly, John; Forker, Caitlin; Holena, Daniel; Wu, Qufei; Lanken, Paul; Christie, Jason; Shashaty, Michael

Background:Receptor interacting protein kinase-3 (RIP3) is a key mediator of necroptosis, a form of regulated cell death recently implicated in murine models of renal ischemia-reperfusion injury and transfusion-associated endothelial injury. The importance of necroptosis in human AKI is unknown. We hypothesized that plasma RIP3 concentrations would be associated with acute kidney injury (AKI) after severe trauma.Methods:We performed a case-control study nested in a prospective cohort of critically ill trauma patients. AKI was defined by AKI Network creatinine criteria within 6 days of presentation. Of 158 cohort subjects, we selected 13 who developed AKI stage 2 or 3, 27 with AKI stage 1, and 40 without AKI. We compared plasma RIP3 concentrations across these groups at presentation and 48h. Since red blood cell (RBC) transfusion is an AKI risk factor, we also tested the association of RBCs transfused during resuscitation with RIP3 levels.Results:Median plasma RIP3 concentration rose more than 10-fold from presentation (15.6 (interquartile range 15.6-41.3) pg/mL) to 48h (164.7 (66.9-300.6) pg/mL; P<0.001). RIP3 concentrations at 48h were associated with AKI stage (no AKI: 144.8 (58.6-234.9) pg/mL; AKI stage 1: 165.8 (43.0-310.9) pg/mL; AKI stage 2-3: 365.5 (155.1-727.5) pg/mL; P=0.010) whereas this association was not seen at presentation (P=0.324). RBC transfusions were also associated with 48-h plasma RIP3 (no RBCs: 99.4 (15.6-166.1) pg/mL; 1-5 units: 182.6 (98.5-274.1) pg/mL;>5 units: 341.8 (150.1-423.8) pg/mL; P<0.001).Conclusions:In critically ill trauma patients, plasma levels of the necroptosis mediator RIP3 at 48h were associated with AKI stage and RBC transfusions.

PURPOSE:To examine whether an Internet-based learning module and small-group debriefing can improve medical trainees' attitudes and communication skills toward patients with substance use disorders (SUDs).METHOD:In 2011-2012, 129 internal and family medicine residents and 370 medical students at two medical schools participated in a cluster randomized controlled trial, which assessed the effect of adding a two-part intervention to the SUDs curricula. The intervention included a self-directed, media-rich Internet-based learning module and a small-group, faculty-led debriefing. Primary study outcomes were changes in self-assessed attitudes in the intervention group (I-group) compared with those in the control group (C-group) (i.e., a difference of differences). For residents, the authors used real-time, Web-based interviews of standardized patients to assess changes in communication skills. Statistical analyses, conducted separately for residents and students, included hierarchical linear modeling, adjusted for site, participant type, cluster, and individual scores at baseline.RESULTS:The authors found no significant differences between the I- and C-groups in attitudes for residents or students at baseline. Compared with those in the C-group, residents, but not students, in the I-group had more positive attitudes toward treatment efficacy and self-efficacy at follow-up (P<.006). Likewise, compared with residents in the C-group, residents in the I-group received higher scores on screening and counseling skills during the standardized patient interview at follow-up (P=.0009).CONCLUSIONS:This intervention produced improved attitudes and communication skills toward patients with SUDs among residents. Enhanced attitudes and skills may result in improved care for these patients.

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.