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IntroductionEnhanced recovery after surgery (ERAS) pathways have emerged as a promising strategy to reduce postoperative opioid use and decrease the risk of developing new persistent opioid use in surgical patients. However, the association between ERAS implementation and discharge opioid prescribing practices is unclear.Study designWe conducted a retrospective observational quasi-experimental study of opioid-naïve patients aged 18+ undergoing cesarean delivery between February 2015 and December 2019 at a large academic center. An interrupted time series analysis (ITSA) was used to model the changes in pain medication prescribing associated with the implementation of ERAS to account for pre-existing temporal trends.ResultsAmong the 1473 patients (out of 2249 total) who underwent cesarean delivery after ERAS implementation, 80.72% received a discharge opioid prescription vs. 95.36% at baseline. Pre-ERAS daily oral morphine equivalents (OME) on the discharge prescription decreased by 0.48 OME each month (p

Rationale: Receptor for advanced glycation end-products (RAGE) is one of the alveolar type I cell-associated proteins in the lung.Objectives: To test the hypothesis that RAGE is a marker of alveolar epithelial type I cell injury.Methods: Rats were instilled intratracheally with 10 mg/kg lipopolysaccharide or hydrochloric acid. RAGE levels were measured in the bronchoalveolar lavage (BAL) and serum in the rats and in the pulmonary edema fluid and plasma from patients with acute lung injury (ALI; n = 22) and hydrostatic pulmonary edema (n = 11).Main Results: In the rat lung injury studies, RAGE was released into the BAL and serum as a single soluble isoform sized approximately 48 kD. The elevated levels of RAGE in the BAL correlated well with the severity of experimentally induced lung injury. In the human studies, the RAGE level in the pulmonary edema fluid was significantly higher than the plasma level (p < 0.0001). The median edema fluid/plasma ratio of RAGE levels was 105 (interquartile range, 55-243). The RAGE levels in the pulmonary edema fluid from patients with ALI were higher than the levels from patients with hydrostatic pulmonary edema (p < 0.05), and the plasma RAGE level in patients with ALI were significantly higher than the healthy volunteers (p < 0.001) or patients with hydrostatic pulmonary edema (p < 0.05).Conclusion: RAGE is a marker of type I alveolar epithelial cell injury based on experimental studies in rats and in patients with ALI. [ABSTRACT FROM AUTHOR]

Objective: Inadequate vein quality or prior harvest precludes use of autologous single segment greater saphenous vein (ssGSV) in many patients with chronic limb-threatening ischemia (CLTI). Predictors of patient outcome after infrainguinal bypass with alternative (non-ssGSV) conduits are not well-understood. We explored whether limb presentation, bypass target, and conduit type were associated with amputation-free survival (AFS) after infrainguinal bypass using alternative conduits., Methods: A single-center retrospective study (2013-2020) was conducted of 139 infrainguinal bypasses performed for CLTI with cryopreserved ssGSV (cryovein) (n = 71), polytetrafluoroethylene (PTFE) (n = 23), or arm/spliced vein grafts (n = 45). Characteristics, Wound, Ischemia, and foot Infection (WIfI) stage, and outcomes were recorded. Multivariable Cox proportional hazards and classification and regression tree analysis modeled predictors of AFS., Results: Within 139 cases, the mean age was 71 years, 59% of patients were male, and 51% of cases were nonelective. More patients undergoing bypass with cryovein were WIfI stage 4 (41%) compared with PTFE (13%) or arm/spliced vein (27%) (P = .04). Across groups, AFS at 2 years was 78% for spliced/arm, 79% for PTFE, and 53% for cryovein (adjusted hazard ratio for cryovein, 2.5; P = .02). Among cases using cryovein, classification and regression tree analysis showed that WIfI stage 3 or 4, age >70 years, and prior failed bypass were predictive of the lowest AFS at 2 years of 36% vs AFS of 58% to 76% among subgroups with less than two of these factors. Although secondary patency at 2 years was worse in the cryovein group (26% vs 68% and 89% in arm/spliced and PTFE groups; P < .01), in patients with tissue loss there was no statistically significant difference in wound healing in the cryovein group (72%) compared with other bypass types (72% vs 87%, respectively; P = .12)., Conclusions: In patients with CLTI lacking suitable ssGSV, bypass with autogenous arm/spliced vein or PTFE has superior AFS compared with cryovein, although data were limited for PTFE conduits for distal targets. Despite poor patency with cryovein, wound healing is achieved in a majority of cases, although it should be used with caution in older patients with high WIfI stage and prior failed bypass, given the low rates of AFS., Competing Interests: Disclosures M.C. is an advisory board member for Abbott Vascular., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Open abdominal aortic aneurysm repair (OAR) is a major vascular procedure that incurs a large physiologic demand, increasing the risk for complications such as postoperative delirium (POD). We sought to characterize POD incidence, identify delirium risk factors, and evaluate the effect of delirium on postoperative outcomes. We hypothesized that POD following OAR would be associated with increased postoperative complications and resource utilization., Methods: This was a retrospective study of all OAR cases from 2012 to 2020 at a single tertiary care center. POD was identified via a validated chart review method based on key words and Confusion Assessment Method assessments. The primary outcome was POD, and secondary outcomes included length of stay, non-home discharge, 90-day mortality, and 1-year survival. Bivariate analysis as appropriate to the data was used to assess the association of delirium with postoperative outcomes. Multivariable binary logistic regression was used to identify risk factors for POD and Cox regression for variables associated with worse 1-year survival., Results: Overall, 198 OAR cases were included, and POD developed in 34% (n = 67). Factors associated with POD included older age (74 vs 69 years; P < .01), frailty (50% vs 28%; P < .01), preoperative dementia (100% vs 32%; P < .01), symptomatic presentation (47% vs 27%; P < .01), preoperative coronary artery disease (44% vs 28%; P = .02), end-stage renal disease (89% vs 32%; P < .01) and Charlson Comorbidity Index score >4 (42% vs 26%; P = .01). POD was associated with 90-day mortality (19% vs 5%; P < .01), non-home discharge (61% vs 30%; P < .01), longer median hospital length of stay (14 vs 8 days; P < .01), longer median intensive care unit length of stay (6 vs 3 days; P < .01), postoperative myocardial infarction (7% vs 2%; P = .045), and postoperative pneumonia (19% vs 8%; P = .01). On multivariable analysis, risk factors for POD included older age, history of end-stage renal disease, lack of epidural, frailty, and symptomatic presentation. A Cox proportional hazards model revealed that POD was associated with worse survival at 1 year (hazard ratio, 3.8; 95% confidence interval, 1.6-9.0; P = .003)., Conclusions: POD is associated with worse postoperative outcomes and increased resource utilization. Future studies should examine the role of improved screening, implementation of delirium prevention bundles, and multidisciplinary care for the most vulnerable patients undergoing OAR., Competing Interests: Disclosures None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Based on data supporting a volume-outcome relationship in elective aortic aneurysm repair, the Society of Vascular Surgery (SVS) guidelines recommend that endovascular aortic repair (EVAR) be localized to centers that perform ≥10 operations annually and have a perioperative mortality and conversion-to-open rate of ≤2% and that open aortic repair (OAR) be localized to centers that perform ≥10 open aortic operations annually and have a perioperative mortality ≤5%. However, the number and distribution of centers meeting the SVS criteria remains unclear. This study aimed to estimate the temporal trends and geographic distribution of Centers Meeting the SVS Aortic Guidelines (CMAG) in the United States., Methods: The SVS Vascular Quality Initiative was queried for all OAR, aortic bypasses, and EVAR from 2011 to 2019. Annual OAR and EVAR volume, 30-day elective operative mortality for OAR or EVAR, and EVAR conversion-to-open rate for all centers were calculated. The SVS guidelines for OAR and EVAR, individually and combined, were applied to each institution leading to a CMAG designation. The proportion of CMAGs by region (West, Midwest, South, and Northeast) were compared by year using a χ 2 test. Temporal trends were estimated using a multivariable logistic regression for CMAG, adjusting by region., Results: Overall, 67,865 patients (49,264 EVAR; 11,010 OAR; 7591 aortic bypasses) at 336 institutions were examined. The proportion of EVAR CMAGs increased nationally by 1.7% annually from 51.6% (n = 33/64) in 2011 to 67.1% (n = 190/283) in 2019 (β = .05; 95% confidence interval [CI], 0.01-0.09; P = .02). The proportion of EVAR CMAGs across regions ranged from 27.3% to 66.7% in 2011 to 63.9% to 72.9% in 2019. In contrast, the proportion of OAR CMAGs has decreased nationally by 1.8% annually from 32.8% (n = 21/64) in 2011 to 16.3% (n = 46/283) in 2019 (β = -.14; 95% CI, -0.19 to -0.10; P < .01). Combined EVAR and OAR CMAGs were even less frequent and decreased by 1.5% annually from 26.6% (n = 17/64) in 2011 to 13.1% (n = 37/283) in 2019 (β = -.12; 95% CI, -0.17 to -0.07; P < .01). In 2019, there was no significant difference in regional variation of the proportion of combined EVAR and OAR CMAGs (P = .82)., Conclusions: Although an increasing proportion of institutions nationally meet the SVS guidelines for EVAR, a smaller proportion meet them for OAR, with a concerning downward trend. These data question whether we can safely offer OAR at most institutions, have important implications about sufficient OAR exposure for trainees, and support regionalization of OAR., Competing Interests: Disclosures None., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: There remains a need to better identify patients at highest risk for developing severe Coronavirus Disease 2019 (COVID-19) as additional waves of the pandemic continue to impact hospital systems. We sought to characterize the association of receptor for advanced glycation end products (RAGE), SARS-CoV-2 nucleocapsid viral antigen, and a panel of thromboinflammatory biomarkers with development of severe disease in patients presenting to the emergency department with symptomatic COVID-19., Methods: Blood samples were collected on arrival from 77 patients with symptomatic COVID-19, and plasma levels of thromboinflammatory biomarkers were measured., Results: Differences in biomarkers between those who did and did not develop severe disease or death 7 days after presentation were analyzed. After adjustment for multiple comparisons, RAGE, SARS-CoV-2 nucleocapsid viral antigen, interleukin (IL)-6, IL-10 and tumor necrosis factor receptor (TNFR)-1 were significantly elevated in the group who developed severe disease (all p <0.05). In a multivariable regression model, RAGE and SARS-CoV-2 nucleocapsid viral antigen remained significant risk factors for development of severe disease (both p <0.05), and each had sensitivity and specificity >80% on cut-point analysis., Discussion: Elevated RAGE and SARS-CoV-2 nucleocapsid viral antigen on emergency department presentation are strongly associated with development of severe disease at 7 days. These findings are of clinical relevance for patient prognostication and triage as hospital systems continue to be overwhelmed. Further studies are warranted to determine the feasibility and utility of point-of care measurements of these biomarkers in the emergency department setting to improve patient prognostication and triage., Competing Interests: LK consulted for Gamma Diagnostics and Cerus Corporation at the time of this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Matthay, Fields, Wick, Jones, Lane, Herrera, Nuñez-Garcia, Gennatas, Hendrickson, Kornblith, Matthay, Kornblith and the COVID-19 Associated Coagulopathy Inflammation Thrombosis (Co-ACIT) Study Group.)

Introduction: Thromboinflammatory complications are well described sequalae of Coronavirus Disease 2019 (COVID-19), and there is evidence of both hyperreactive platelet and inflammatory neutrophil biology that contributes to the thromoinflammatory milieu. It has been demonstrated in other thromboinflammatory diseases that the circulating environment may affect cellular behavior, but what role this environment exerts on platelets and neutrophils in COVID-19 remains unknown. We tested the hypotheses that 1) plasma from COVID-19 patients can induce a prothrombotic platelet functional phenotype, and 2) contents released from platelets (platelet releasate) from COVID-19 patients can induce a proinflammatory neutrophil phenotype., Methods: We treated platelets with COVID-19 patient and disease control plasma, and measured their aggregation response to collagen and adhesion in a microfluidic parallel plate flow chamber coated with collagen and thromboplastin. We exposed healthy neutrophils to platelet releasate from COVID-19 patients and disease controls and measured neutrophil extracellular trap formation and performed RNA sequencing., Results: We found that COVID-19 patient plasma promoted auto-aggregation, thereby reducing response to further stimulation ex-vivo . Neither disease condition increased the number of platelets adhered to a collagen and thromboplastin coated parallel plate flow chamber, but both markedly reduced platelet size. COVID-19 patient platelet releasate increased myeloperoxidasedeoxyribonucleic acid complexes and induced changes to neutrophil gene expression., Discussion: Together these results suggest aspects of the soluble environment circulating platelets, and that the contents released from those neutrophil behavior independent of direct cellular contact., Competing Interests: LK is on the scientific advisory board for Cerus and Gamma-Prime Fibrinogen, and is a family member of a founder of Capture Diagnostics. MN serves on the scientific advisory board of Haima Therapeutics, has received personal fees from Haemonetics, Takeda, and Janssen Pharmaceuticals, and has received travel support from Meredian Biosciences. He has received grants from Haemonetics and Instrumentation Laboratories. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fields, Andraska, Kaltenmeier, Matthay, Herrera, Nuñez-Garcia, Jones, Wick, Liu, Luo, Yu, Matthay, Hendrickson, Bainton, Barrett, Berger, Neal, Kornblith and the COVID-19 Associated Coagulopathy Inflammation and Thrombosis (Co-ACIT) Study Group.)

Objective: Racial and ethnic disparities have been well-documented in the outcomes for chronic limb threatening ischemia (CLTI). One purported explanation has been the disease severity at presentation. We hypothesized that the disparities in major adverse limb events (MALE) after peripheral vascular intervention (PVI) for CLTI would persist despite controlling for disease severity at presentation using the WIfI (Wound, Ischemia, foot Infection) stage., Methods: The Vascular Quality Initiative PVI dataset (2016-2021) was queried for CLTI. Patients were excluded if they were missing the WIfI stage. The primary end point was the incidence of 1-year MALE, defined as major amputation (through the tibia or fibula or more proximally) or reintervention (endovascular or surgical) of the initial treatment limb. A multivariate hierarchical Fine-Gray analysis was performed, controlling for hospital variation, competing risk of death, and presenting WIfI stage, to assess the independent association of Black/African American race and Latinx/Hispanic ethnicity with MALE. A Cox proportional hazard regression model was used for the 1-year survival analysis., Results: Overall, 47,830 patients (60%) had had WIfI scores reported (73% White, 20% Black, and 7% Latinx). The 1-year unadjusted cumulative incidence of MALE was 13.1% (95% confidence interval [CI], 12.6%-13.5%) for White, 14.3% (95% CI, 13.5%-15.3%) for Black, and 17.0% (95% CI, 15.3%-18.9%) for Latinx patients. On bivariate analysis, the occurrence of MALE was significantly associated with younger age, Black race, Latinx ethnicity, coronary artery disease, cerebrovascular disease, congestive heart failure, hypertension, diabetes, dialysis, intervention level, any prior minor or major amputation, and WIfI stage (P < .001). The cumulative incidence of 1-year MALE increased by increasing WIfI stage: stage 1, 11.7% (95% CI, 10.9%-12.4%); stage 2, 12.4% (95% CI, 11.8%-13.0%); stage 3, 14.8% (95% CI, 13.8%-15.8%); and stage 4, 15.4% (95% CI, 14.3%-16.6%). The cumulative incidence also increased by intervention level: inflow, 10.7% (95% CI, 9.8%-11.7%), femoropopliteal, 12.3% (95% CI, 11.7%-12.9%); and infrapopliteal, 14.1% (95% CI, 13.5%-14.8%). After adjustment for WIfI stage only, Black race (subdistribution hazard ratio [SHR], 1.30; 95% CI, 1.17-1.44; P < .001) and Latinx ethnicity (SHR, 1.58; 95% CI, 1.37-1.81; P < .001) were associated with an increased 1-year hazard of MALE compared with White race. On adjusted multivariable analysis, MALE disparities persisted for Black/African American race (SHR, 1.12; 95% CI, 1.01-1.25; P = .028) and Latinx/Hispanic ethnicity (SHR, 1.34; 95% CI, 1.16-1.54; P < .001) compared with White race., Conclusions: Black/African American and Latinx/Hispanic patients had a higher associated hazard of MALE after PVI for CLTI compared with White patients despite an adjustment for WIfI stage at presentation. These results suggest that disease severity at presentation does not account for disparities in outcomes. Further work should focus on better understanding the underlying mechanisms for disparities in historically marginalized racial and ethnic groups presenting with CLTI., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients undergoing open or endovascular infrainguinal revascularization are at an elevated risk for postoperative cardiovascular complications due to high rates of comorbidities and the physiologic stress of surgery. Transfusions are known to be associated with adverse events but knowledge of specific risks associated with transfusion timing, product type, and long-term outcomes while accounting for preoperative cardiovascular risk factors is not well understood in this population. This study aimed to characterize the association of intraoperative and perioperative transfusion, anemia, and cardiovascular risk factors with cardiovascular events and mortality in patients undergoing infrainguinal revascularization., Methods: A single-center retrospective study was performed on 564 infrainguinal revascularization procedures, including both open (n = 250) and endovascular (n = 314) approaches (2016-2020). Comprehensive clinical data were collected including patient demographics, cardiovascular risk factors, preoperative hemoglobin, and detailed transfusion data. Multivariable logistic regression tested the association of transfusions with composite 30-day outcomes of cardiac complications (postoperative myocardial infarction [postop-MI], congestive heart failure, or dysrhythmia) and with major adverse cardiovascular events (MACE-postop-MI or death). Kaplan-Meier analysis and Cox proportional hazard modeling examined the association of transfusions, anemia, and cardiovascular risk factors with mortality up to 1 year., Results: Intraoperative transfusion was performed in 15% of cases and 13% underwent transfusion in the early postoperative period. Intraoperative transfusion was associated with higher Revised Cardiac Risk Index (RCRI), lower preoperative hemoglobin, increased blood loss, and open procedures (all P < 0.05). Within each RCRI score, intraoperative transfusion was associated with 2-4-fold increased MACE at 30 days. Intraoperative packed red blood cells transfusion and early postoperative packed red blood cells transfusion was associated with more than 2-fold adjusted odds of any cardiovascular complication and intraoperative transfusion was also associated with MACE (all P < 0.05). Intraoperative transfusion was associated with mortality at 1 year on unadjusted analysis, but after adjustment for RCRI, age, and preoperative hemoglobin, only RCRI scores of 2 and 3+ and preoperatively hemoglobin remained significant risk factors for mortality., Conclusions: Intraoperative and early perioperative transfusions are strongly associated with worse cardiovascular outcomes after infrainguinal revascularization. These findings may have a prognostic value for further risk stratifying patients perioperatively at a high risk for complications. However, prospective studies are needed to elucidate whether optimizing transfusion strategies mitigates these risks., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Post-operative delirium (POD) is common yet often underdiagnosed following vascular surgery. Elderly patients with advanced peripheral artery disease may be at particular risk for POD yet understanding of the clinical predictors and impact of POD is incomplete. We sought to identify POD predictors and associated resource utilization after infrainguinal lower extremity bypass., Methods: This single center retrospective analysis included all infrainguinal bypass cases performed for peripheral arterial disease from 2012-2020. The primary outcome was inpatient POD. Delirium sequelae were also evaluated. Key secondary outcomes were length of stay, nonhome discharge, readmission, 30-day amputation, post-operative myocardial infarction, mortality, and 2-year survival. Regression analysis was used to evaluate risk factors for delirium in addition to association with 2-year survival and amputation free survival., Results: Among 420 subjects undergoing infrainguinal lower extremity bypass, 105 (25%) developed POD. Individuals with POD were older and more likely to have non-elective surgery (P < 0.05). On multivariable analysis, independent predictors of POD were age 60-89 years old, chronic limb threatening ischemia, female sex, and nonelective procedure. Consultations for POD took place for 25 cases (24%); 13 (52%) were with pharmacists, and only 4 (16%) resulted in recommendations. The average length of stay for those with POD was higher (17 days vs. 9 days; P < 0.001). POD was associated with increased non-home discharge (61.8% vs. 22.1%; P < 0.001), 30-day major amputation (6.7% vs. 1.6%; P < 0.01), 30-day postoperative myocardial infarction (11.4% vs. 4.1%; P < 0.01), and 90-day mortality (7.6% vs. 2.9%; P = 0.03). Survival at 2 years was lower in those with delirium (89% vs. 75%; P < 0.001). In a Cox proportional hazards model, delirium was independently associated with decreased survival (HR = 2.0; 95% CI = 1.15-3.38; P = 0.014) and decreased major-amputation free survival (HR = 1.9; 95% CI = 1.18-2.96; P = 0.007)., Conclusions: POD is common following infrainguinal lower extremity bypass and is associated with other adverse post-operative outcomes and increased resource utilization, including increased hospital length of stay, nonhome discharge, and worse 2-year survival. Future studies should evaluate the role of routine multidisciplinary care for high-risk patients to improve perioperative outcomes for vulnerable older adults undergoing infrainguinal lower extremity bypass., (Published by Elsevier Inc.)

Background: Posttraumatic venous thromboembolism (VTE) remains prevalent in severely injured patients despite chemoprophylaxis. Importantly, although platelets are central to thrombosis, they are not routinely targeted in prevention of posttraumatic VTE. Furthermore, platelets from injured patients show ex vivo evidence of increased activation yet impaired aggregation, consistent with functional exhaustion. However, the relationship of this platelet functional phenotype with development of posttraumatic VTE is unknown. We hypothesized that, following injury, impaired ex vivo platelet aggregation (PA) is associated with the development of posttraumatic VTE., Methods: We performed a secondary analysis of 133 severely injured patients from a prospective observational study investigating coagulation and inflammation (2011-2019). Platelet aggregation in response to stimulation with adenosine diphosphate (ADP), collagen, and thrombin was measured at presentation (preresuscitation) and 24 hours (postresuscitation). Viscoelastic clot strength and lysis were measured in parallel by thromboelastography. Multivariable regression examined relationships between PA at presentation, 24 hours, and the change (δ) in PA between presentation and 24 hours with development of VTE., Results: The 133 patients were severely injured (median Injury Severity Score, 25), and 14% developed VTE (all >48 hours after admission). At presentation, platelet count and PA were not significantly different between those with and without incident VTE. However, at 24 hours, those who subsequently developed VTE had significantly lower platelet counts (126 × 10 9 /L vs. 164 × 10 9 /L, p = 0.01) and lower PA in response to ADP ( p < 0.05), collagen ( p < 0.05), and thrombin ( p = 0.06). Importantly, the magnitude of decrease in PA (δ) from presentation to 24 hours was independently associated with development of VTE (adjusted odds ratios per 10 aggregation unit decrease: δ-ADP, 1.31 [ p = 0.03]; δ-collagen, 1.36 [ p = 0.01]; δ-thrombin, 1.41 [ p < 0.01])., Conclusion: Severely injured patients with decreasing ex vivo measures of PA despite resuscitation have an increased risk of developing VTE. This may have implications for predicting development of VTE and for studying platelet targeted chemoprophylaxis regimens., Level of Evidence: Prognostic/Epidemiological; Level III., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Autopsy and biomarker studies suggest that endotheliopathy contributes to coronavirus disease (COVID-19)-associated acute respiratory distress syndrome. However, the effects of COVID-19 on the lung endothelium are not well defined. We hypothesized that the lung endotheliopathy of COVID-19 is caused by circulating host factors and direct endothelial infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objectives: We aimed to determine the effects of SARS-CoV-2 or sera from patients with COVID-19 on the permeability and inflammatory activation of lung microvascular endothelial cells. Methods: Human lung microvascular endothelial cells were treated with live SARS-CoV-2; inactivated viral particles; or sera from patients with COVID-19, patients without COVID-19, and healthy volunteers. Permeability was determined by measuring transendothelial resistance to electrical current flow, where decreased resistance signifies increased permeability. Inflammatory mediators were quantified in culture supernatants. Endothelial biomarkers were quantified in patient sera. Measurements and Main Results: Viral PCR confirmed that SARS-CoV-2 enters and replicates in endothelial cells. Live SARS-CoV-2, but not dead virus or spike protein, induces endothelial permeability and secretion of plasminogen activator inhibitor 1 and vascular endothelial growth factor. There was substantial variability in the effects of SARS-CoV-2 on endothelial cells from different donors. Sera from patients with COVID-19 induced endothelial permeability, which correlated with disease severity. Serum levels of endothelial activation and injury biomarkers were increased in patients with COVID-19 and correlated with severity of illness. Conclusions: SARS-CoV-2 infects and dysregulates endothelial cell functions. Circulating factors in patients with COVID-19 also induce endothelial cell dysfunction. Our data point to roles for both systemic factors acting on lung endothelial cells and viral infection of endothelial cells in COVID-19-associated endotheliopathy.

Objective: Venous thromboembolism (VTE) is an important cause of postoperative morbidity and mortality. However, the reported incidence after major vascular surgery has ranged from as low as 1% to >10%. Furthermore, little is known about optimal chemoprophylaxis regimens or rates of postdischarge VTE in this population. In the present study, we aimed to better characterize the rates of in-hospital and postdischarge VTE after major vascular surgery, the role of chemoprophylaxis timing, and the association of VTE with mortality., Methods: A single-center retrospective study of 1449 major vascular operations (2013-2020) was performed and included 189 endovascular abdominal aortic aneurysm repairs (13%), 169 thoracic endovascular aortic aneurysm repairs (12%), 318 open aortic operations (22%), 640 lower extremity bypasses (44%), and 133 femoral endarterectomies (9%). The baseline characteristics, anticoagulant and antiplatelet medications, and outcomes were abstracted from an electronic database with medical record auditing. Postoperative VTE (pulmonary embolism and deep vein thrombosis) within 90 days of surgery was classified by the location, symptoms, and treatment. A cut point analysis using Youden's index identified the most VTE discriminating timing of chemoprophylaxis (including therapeutic vs prophylactic anticoagulant and antiplatelet medications) and Caprini score. Multivariable logistic regression was used to test the association of VTE with chemoprophylaxis timing, Caprini score, and additional risk factors. Cox proportional hazard modeling was used to measure the association between VTE and mortality., Results: The overall VTE incidence was 3.4% (65% deep vein thrombosis; 25% pulmonary embolism; 10% both), and 37% had occurred after discharge. The rate of symptomatic VTE was 2.4%, which was lowest for endovascular abdominal aortic aneurysm repair (0.0%) and highest for open aortic surgery (4.1%; P = .02). Those who had developed VTE had had a longer length of stay, higher rates of end-stage renal disease and prior VTE, and higher Caprini scores (8 vs 5 points; P < .01 for all). Those who had developed VTE were also more likely to have received ≥2 U of blood postoperatively, required an unplanned return to the operating room, had delayed chemoprophylaxis, anticoagulation, and/or antiplatelet initiation of >4 days postoperatively, and had increased 90-day mortality (P < .01 for all). A Caprini score of ≥7 (29% of patients) was associated with postdischarge VTE (2.6% vs 0.7%; P = .01), and chemoprophylaxis, anticoagulation, and antiplatelet timing of >4 days was associated with an increased adjusted odds of VTE (odds ratio, 2.4; 95% confidence interval, 1.1-4.9). Although no fatal VTEs were identified, VTE was an independent predictor of 90-day mortality (adjusted hazard ratio, 2.7; 95% confidence interval, 1.3-5.9)., Conclusions: These data have shown that patients undergoing major vascular surgery are particularly prone to the development of VTE, with frequent hypercoagulable comorbidities. The earlier initiation of chemoprophylaxis was associated with a reduced risk of VTE development. Furthermore, the postdischarge VTE rates might reach thresholds warranting postdischarge chemoprophylaxis, especially for patients with a Caprini score of ≥7., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to characterize changes in firearm injuries at 5 level 1 trauma centers in Northern California in the 12 months following the start of the COVID-19 pandemic compared with the preceding 4 years, accounting for regional variations and seasonal trends., Summary and Background Data: Increased firearm injuries have been reported during the early peaks of the COVID-19 pandemic despite shelter-in-place restrictions. However, these data are overwhelmingly from singlecenter studies, during the initial phase of the pandemic prior to lifting of shelter-in-place restrictions, or do not account for seasonal trends., Methods: An interrupted time-series analysis (ITSA) of all firearm injuries presenting to 5 adult level 1 trauma centers in Northern California was performed (January 2016to February 2021). ITSA modeled the association of the onset of the COVID-19 pandemic (March 2020) with monthly firearm injuries using the ordinary least-squares method, included month indicators to adjust for seasonality, and specified lags of up to 12 months to account for autocorrelation., Results: Prior to the start of COVID-19, firearm injuries averaged (±SD) of 86 (±16) and were decreasing by 0.5/month (P < 0.01). The start of COVID- 19 (March 2020) was associated with an alarming increase of 39 firearm injuries/month (P < 0.01) followed by an ongoing rise of 3.5/mo (P < 0.01). This resulted in an average of 130 (±26) firearm injuries/month during the COVID-19 period and included 8 of the 10 highest monthly firearm injury rates in the past 5 years., Conclusions: These data highlight an alarming escalation in firearm injuries in the 12 months following the onset of the COVID-19 pandemic in Northern California. Additional studies and resources are needed to better understand and address this parallel public health crisis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The earliest measurable changes to postinjury platelet biology may be in the platelet transcriptome, as platelets are known to carry messenger ribonucleic acids (RNAs), and there is evidence in other inflammatory and infectious disease states of differential and alternative platelet RNA splicing in response to changing physiology. Thus, the aim of this exploratory pilot study was to examine the platelet transcriptome and platelet RNA splicing signatures in trauma patients compared with healthy donors., Methods: Preresuscitation platelets purified from trauma patients (n = 9) and healthy donors (n = 5) were assayed using deep RNA sequencing. Differential gene expression analysis, weighted gene coexpression network analysis, and differential alternative splicing analyses were performed. In parallel samples, platelet function was measured with platelet aggregometry, and clot formation was measured with thromboelastography., Results: Differential gene expression analysis identified 49 platelet RNAs to have differing abundance between trauma patients and healthy donors. Weighted gene coexpression network analysis identified coexpressed platelet RNAs that correlated with platelet aggregation. Differential alternative splicing analyses revealed 1,188 splicing events across 462 platelet RNAs that were highly statistically significant (false discovery rate <0.001) in trauma patients compared with healthy donors. Unsupervised principal component analysis of these platelet RNA splicing signatures segregated trauma patients in two main clusters separate from healthy controls., Conclusion: Our findings provide evidence of finetuning of the platelet transcriptome through differential alternative splicing of platelet RNA in trauma patients and that this finetuning may have relevance to downstream platelet signaling. Additional investigations of the trauma platelet transcriptome should be pursued to improve our understanding of the platelet functional responses to trauma on a molecular level., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Introduction: Pain management is critical for optimal recovery after trauma. Previous work at our institution revealed differences in pain assessment by patient language, which may impact management. This study aimed to understand differences in discharge opioid prescribing for trauma patients with limited English proficiency (LEP)., Methods: We conducted a cross-sectional study of adult trauma patients discharged to the community from a diverse, urban level 1 trauma center in 2018. Opioid prescriptions were obtained from discharge pharmacy records and converted to standard oral morphine equivalents (OMEs). Multivariable logistic and quantile regression was used to examine the relationship between LEP, opioid prescriptions, and OMEs at discharge, controlling for demographic and clinical characteristics., Results: Of 1,419 patients included in this study, 83% were English proficient (EP) and 17% were LEP. At discharge, 56% of EP patients received an opioid prescription, compared with 41% of LEP patients. In multivariable models, EP patients were 1.63 times more likely to receive any opioid prescription (95% CI, 1.17-2.25; p = 0.003). Mean OME was 147 for EP and 94 for LEP patients. In multivariable models, the difference between EP and LEP patients was 40 OMEs (95% CI, 21.10-84.22; p = 0.004). In adjusted quantile regression models, differences in total OMEs increased with the amount of OMEs prescribed. There was no difference in OMEs at the 20th and 40th percentile of total OMEs, but LEP patients received 26 fewer OMEs on average at the 60th percentile (95% CI, -3.23 to 54.90; p = 0.081) and 45 fewer OMEs at the 80th percentile (95% CI, 5.48-84.48; p = 0.026)., Conclusion: Limited English proficiency patients with traumatic injuries were less likely to receive any opioid prescription and were prescribed lower quantities of opiates, which could contribute to suboptimal pain management and recovery. Addressing these disparities is an important focus for future quality improvement efforts., Level of Evidence: Care Management, level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite the widespread institution of modern massive transfusion protocols with balanced blood product ratios, survival for patients with traumatic hemorrhage receiving ultramassive transfusion (UMT) (defined as ≥20 U of packed red blood cells [RBCs]) in 24 hours) remains low and resource consumption remains high. Therefore, we aimed to identify factors associated with mortality in trauma patients receiving UMT in the modern resuscitation era., Methods: An Eastern Association for the Surgery of Trauma multicenter retrospective study of 461 trauma patients from 17 trauma centers who received ≥20 U of RBCs in 24 hours was performed (2014-2019). Multivariable logistic regression and Classification and Regression Tree analysis were used to identify clinical characteristics associated with mortality., Results: The 461 patients were young (median age, 35 years), male (82%), severely injured (median Injury Severity Score, 33), in shock (median shock index, 1.2; base excess, -9), and transfused a median of 29 U of RBCs, 22 U of fresh frozen plasma (FFP), and 24 U of platelets (PLT). Mortality was 46% at 24 hours and 65% at discharge. Transfusion of RBC/FFP ≥1.5:1 or RBC/PLT ≥1.5:1 was significantly associated with mortality, most pronounced for the 18% of patients who received both RBC/PLT and RBC/FFP ≥1.5:1 (odds ratios, 3.11 and 2.81 for mortality at 24 hours and discharge; both p < 0.01). Classification and Regression Tree identified that age older than 50 years, low initial Glasgow Coma Scale, thrombocytopenia, and resuscitative thoracotomy were associated with low likelihood of survival (14-26%), while absence of these factors was associated with the highest survival (71%)., Conclusion: Despite modern massive transfusion protocols, one half of trauma patients receiving UMT are transfused with either RBC/FFP or RBC/PLT in unbalanced ratios ≥1.5:1, with increased associated mortality. Maintaining focus on balanced ratios during UMT is critical, and consideration of advanced age, poor initial mental status, thrombocytopenia, and resuscitative thoracotomy can aid in prognostication., Level of Evidence: Prognostic, level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The large-scale social distancing efforts to reduce SARS-CoV-2 transmission have dramatically changed human behaviors associated with traumatic injuries. Trauma centers have reported decreases in trauma volume, paralleled by changes in injury mechanisms. We aimed to quantify changes in trauma epidemiology at an urban Level I trauma center in a county that instituted one of the earliest shelter-in-place orders to inform trauma care during future pandemic responses., Methods: A single-center interrupted time-series analysis was performed to identify associations of shelter-in-place with trauma volume, injury mechanisms, and patient demographics in San Francisco, California. To control for short-term trends in trauma epidemiology, weekly level data were analyzed 6 months before shelter-in-place. To control for long-term trends, monthly level data were analyzed 5 years before shelter-in-place., Results: Trauma volume decreased by 50% in the week following shelter-in-place (p < 0.01), followed by a linear increase each successive week (p < 0.01). Despite this, trauma volume for each month (March-June 2020) remained lower compared with corresponding months for all previous 5 years (2015-2019). Pediatric trauma volume showed similar trends with initial decreases (p = 0.02) followed by steady increases (p = 0.05). Reductions in trauma volumes were due entirely to changes in nonviolent injury mechanisms, while violence-related injury mechanisms remained unchanged (p < 0.01)., Conclusion: Although the shelter-in-place order was associated with an overall decline in trauma volume, violence-related injuries persisted. Delineating and addressing underlying factors driving persistent violence-related injuries during shelter-in-place orders should be a focus of public health efforts in preparation for future pandemic responses., Level of Evidence: Epidemiological study, level III., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Altered postinjury platelet behavior is recognized in the pathophysiology of trauma-induced coagulopathy (TIC), but the mechanisms remain largely undefined. Studies suggest that soluble factors released by injury may inhibit signaling pathways and induce structural changes in circulating platelets. Given this, we sought to examine the impact of treating healthy platelets with plasma from injured patients. We hypothesized that healthy platelets treated ex-vivo with plasma from injured patients with shock would impair platelet aggregation, while treatment with plasma from injured patients with significant injury burden, but without shock, would enhance platelet aggregation., Methods: Plasma samples were isolated from injured patients (pretransfusion) and healthy donors at a Level I trauma center and stored at -80°C. Plasma samples from four separate patients in each of the following stratified clinical groups were used: mild injury/no shock (injury severity score [ISS] 2-15, base excess [BE]>-6), mild injury/with shock (ISS 2-15, BE≤-6), severe injury/no shock (ISS>25, BE>-6), severe injury/with shock (ISS>25, BE≤-6), minimal injury (ISS 0/1, BE>-6), and healthy. Platelets were isolated from three healthy adult males and were treated with plasma for 30 min. Aggregation was stimulated with a thrombin receptor agonist and measured via multiple-electrode platelet aggregometry. Data were normalized to HEPES Tyrode's (HT) buffer-only treated platelets. Associations of plasma treatment groups with platelet aggregation measures were tested with Mann-Whitney U tests., Results: Platelets treated with plasma from patients with shock (regardless of degree of injury) had significantly impaired thrombin-stimulated aggregation compared with platelets treated with plasma from patients without shock (P = 0.002). Conversely, platelets treated with plasma from patients with severe injury, but without shock, had amplified thrombin-stimulated aggregation (P = 0.030)., Conclusion: Shock-mediated soluble factors impair platelet aggregation, and tissue injury-mediated soluble factors amplify platelet aggregation. Future characterization of these soluble factors will support development of novel treatments of TIC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Background: Mobilization of intra and extracellular calcium is required for platelet activation, aggregation, and degranulation. However, the importance of alterations in the calcium-platelet axis after injury is unknown. We hypothesized that in injured patients, in vivo initial calcium concentrations (pretransfusion) predict ex vivo platelet activation and aggregation, viscoelastic clot strength, and transfusion of blood products. We additionally hypothesized that increasing calcium concentrations ex vivo increases the expression of platelet activation surface receptors and platelet aggregation responses to agonist stimulation in healthy donor blood., Methods: Blood samples were collected from 538 trauma patients on arrival to the emergency department. Standard assays (including calcium), platelet aggregometry (PA) and thromboelastometry (ROTEM) were performed. In PA, platelet activation (prestimulation impedance [Ω]) and aggregation responses to agonist stimulation (area under the aggregation curve [AUC]) with adenosine diphosphate (ADP), thrombin receptor-activating peptide, arachidonic acid (AA), and collagen (COL) were measured. Multivariable regression tested the associations of calcium with PA, ROTEM, and transfusions. To further examine the calcium-platelet axis, calcium was titrated in healthy blood. Platelet aggregometry and ROTEM were performed, and expression of platelet glycoprotein IIb/IIIa and P-selectin was measured by flow cytometry., Results: The patients were moderately injured with normal calcium and platelet counts. Higher calcium on arrival (pretransfusion) was independently associated with increased platelet activation (prestimulation, Ω; p < 0.001), aggregation (ADP-stimulated, AUC; p = 0.002; thrombin receptor-activating peptide-stimulated, AUC; p = 0.038), and clot strength (ROTEM max clot firmness; p < 0.001), and inversely associated with 24-hour transfusions of blood, plasma, and platelets (all p < 0.005). Up-titrating calcium in healthy blood increased platelet activation (prestimulation, Ω; p < 0.001), aggregation (ADP, AA, COL-stimulated AUCs; p < 0.050), and expression of P-selectin (p = 0.003)., Conclusion: Initial calcium concentrations (pretransfusion) are independently associated with platelet activation, aggregation, clot-strength, and transfusions after injury. These changes may be mediated by calcium driven expression of surface receptors necessary for platelet activation and aggregation. However, the therapeutic benefit of early, empiric calcium repletion in trauma patients remains undefined., Level of Evidence: Prognostic, level V.

Background: Platelet behavior in trauma-induced coagulopathy is poorly understood. Injured patients have impaired platelet aggregation (dysfunction) in ex vivo agonist-stimulated platelet aggregometry (PA). However, PA assumes that platelets are inactivated before ex vivo stimulated aggregation, which may be altered by injury. We hypothesized that following trauma, platelet aggregation (area under the curve) is decreased regardless of injury burden, but that (1) minor injury is associated with an increased baseline electrical impedance, characteristic of a functional platelet phenotype (platelets that activate in response to injury), and that (2) severe injury is not associated with an increased baseline electrical impedance, characteristic of a dysfunctional phenotype (platelets that do not activate well in response to injury) compared with healthy controls., Methods: Blood from 458 trauma patients and 30 healthy donors was collected for PA. Baseline electrical impedance (Ω); platelet aggregation stimulated by adenosine diphosphate, collagen, thrombin, and arachidonic acid; and rotational thromboelastometry were measured. Multivariate regression was performed to identify associations of PA measures with blood transfusion., Results: Compared with healthy controls, injured patients had impaired platelet aggregation in response to ex vivo stimulation, regardless of injury burden. However, minorly injured patients had increased endogenous platelet activation (baseline electrical impedance, Ω: with shock, p = 0.012; without shock, p = 0.084), but severely injured patients did not have significant increases in endogenous platelet activation (baseline electrical impedance, Ω: with shock, p = 0.86; without shock, p = 0.37). For every 10 Ω increase in baseline electrical impedance, there was an 8% decrease in units of blood transfused in the first 24 h (-0.08; confidence interval, -0.14 to -0.02; p = 0.015)., Conclusion: Injury and shock confer differential patterns of platelet aggregation in PA. Minor injury overestimates the presence of platelet dysfunction, while severe injury induces a truly dysfunctional phenotype-platelets that do not activate nor aggregate appropriately after injury. This is consequential in improving accurate phenotyping of postinjury platelet behavior for platelet-based therapeutics., Level of Evidence: Prognostic, level IV.

Background: The mechanisms of aberrant circulating platelet behavior following injury remain unclear. Platelets retain megakaryocyte immature ribonucleic acid (RNA) splicing and protein synthesis machinery to alter their functions based on physiologic signals. We sought to identify fluctuating platelet-specific RNA transcripts in cell-free plasma (CFP) from traumatic brain injury (TBI) patients as proof-of-concept for using RNA sequencing to improve our understanding of postinjury platelet behavior. We hypothesized that we could identify differential expression of activated platelet-specific spliced RNA transcripts from CFP of patients with isolated severe fatal TBI (fTBI) compared with minimally injured trauma controls (t-controls), filtered by healthy control (h-control) data sets., Methods: High-read depth RNA sequencing was applied to CFP from 10 patients with fTBI (Abbreviated Injury Scale [AIS] for head ≥3, AIS for all other categories <3, and expired) and five t-controls (Injury Severity Score ≤1, and survived). A publicly available CFP RNA sequencing data set from 23 h-controls was used to determine the relative steady state of splice-form RNA transcripts discoverable in CFP. Activated platelet-specific spliced RNA transcripts were derived from studies of ex vivo platelet activation and identified by splice junction presence greater than 1.5-fold or less than 0.67-fold ex vivo nonactivated platelet-specific RNA transcripts., Results: Forty-two differentially spliced activated platelet-specific RNA transcripts in 34 genes were altered in CFP from fTBI patients (both upregulated and downregulated)., Conclusion: We have discovered differentially expressed activated platelet-specific spliced RNA transcripts present in CFP from isolated severe fTBI patients that are upregulated or downregulated compared with minimally injured trauma controls. This proof-of-concept suggests that a pool of immature platelet RNAs undergo splicing events after injury for presumed modulation of platelet protein products involved in platelet function. This validates our exploration of injury-induced platelet RNA transcript modulation as an upstream "liquid biopsy" to identify novel postinjury platelet biology and treatment targets for aberrant platelet behavior., Level of Evidence: Diagnostic tests, level V.

The endothelial exocytosis of high-molecular-weight multimeric von Willebrand factor (vWF) may occur in critical illness states, including trauma and sepsis, leading to the sustained elevation and altered composition of plasma vWF. These critical illnesses involve the common process of sympathoadrenal activation and loss of the endothelial glycocalyx. As a prothrombotic and proinflammatory molecule that interacts with the endothelium, the alterations exhibited by vWF in critical illness have been implicated in the development and damaging effects of downstream pathologies, such as disseminated intravascular coagulation and systemic inflammatory response syndrome. Given the role of vWF in these pathologies, there has been a recent push to further understand how the molecule may be involved in the pathophysiology of related diseases, such as trauma-induced coagulopathy and acute renal injury, which are also known to develop secondarily to critical illness states. Elucidation of the role of vWF across the broader spectrum of generalized pathologies may provide a basis for the development of novel preventative and restorative measures, while also bolstering the scaffold of more widely used treatments, such as the administration of plasma-containing blood products., (© 2020 AABB.)

New evidence indicates that neural mechanisms can down-regulate acute inflammation. In these studies, we tested the potential role of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in a rodent model of acid-induced acute lung injury. We first determined that the alpha7 nAChR was expressed by alveolar macrophages and lung epithelial cells. Then, using an acid-induced acute lung injury mouse model, we found that nicotine, choline, and PNU-282,987 (a specific alpha7 nAChR agonist) decreased excess lung water and lung vascular permeability, and reduced protein concentration in the bronchoalveolar lavage (BAL). Deficiency of alpha7 nAChR resulted in a 2-fold increase in excess lung water and lung vascular permeability. The reduction of proinflammatory cytokines (macrophage inflammatory protein-2 and TNF-alpha) in the BAL with nicotine probably resulted from the suppression of NF-kappaB activation in alveolar macrophages. The beneficial effect of nicotine was also tested in rat model of acid-induced acute lung injury in which BAL protein and receptor for advanced glycation end products (RAGE), a marker of type I cell injury, were reduced by nicotine treatment. These results indicate that activation of alpha7 nAChR may provide a new therapeutic pathway for the treatment of acute lung injury.