Predictors of Massive Transfusion Protocol Initiation Among Trauma Patients Transported From the Scene Via Flight Emergency Management Services.

OBJECTIVE: Early identification of the subset of trauma patients with acute hemorrhage who require resuscitation via massive transfusion protocol (MTP) initiation is vital because such identification can ensure the availability of resuscitation products immediately upon hospital arrival and result in improved clinical outcomes, including reduced mortality. However, there are currently few studies on the predictors of MTP in the unique setting of flight transport. METHODS: This was a retrospective study of adult trauma patients transported from the scene via flight to 6 trauma centers between March 1, 2019, and January 21, 2021. Patients were included if they had emergency medical service vitals documented. The variables collected included demographics, comorbidities, cause of injury, body regions injured, in-flight treatments, and transport vitals. The primary outcome was MTP initiated by the receiving hospital. RESULTS: A total of 212 patients were included, of whom 16 (8%) had MTP initiated. During flight transport, 24 (11%) received whole blood, 9 (4%) received packed red blood cells, 11 (5%) had a tourniquet placed, and 5 (2%) received tranexamic acid. In adjusted analyses, receiving whole blood during transport (odds ratio [OR] = 8.52, P < .01), systolic blood pressure ≤ 90 mm Hg (OR = 8.07, P < .01), and a Glasgow Coma Scale score < 13 (OR = 8.38, P < .01) were independently associated with MTP. CONCLUSIONS: This retrospective cohort study showed that 3 factors readily available in the flight setting-receipt of whole blood, systolic blood pressure, and Glasgow Coma Scale score-are strong predictors of MTP at the receiving facility, particularly when considered in aggregate.

Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study.

OBJECTIVE: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. BACKGROUND: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. METHODS: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. RESULTS: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P <0.05). After controlling for center, age, sex, MOI, and injury severity score, we found no differences in the rates of acute kidney injury, deep vein thrombosis/pulmonary embolism or pulmonary complications. WB patients were 9% less likely to experience bleeding complications and were 48% less likely to die than BCT patients ( P <0.0001). CONCLUSIONS: Compared with BCT, the use of WB was associated with a 48% reduction in mortality in trauma patients. Our study supports the use of WB use in the resuscitation of trauma patients.

An Educational Outreach Program: A Trauma System's 5-Year Experience.

BACKGROUND: The American College of Surgeons Committee on Trauma requires Level I and II trauma centers to provide educational outreach to lower-level facilities. Although outreach is a required part of any trauma system, very little is published on the resources required for a successful program. OBJECTIVE: The purpose of this article is to provide a comprehensive roadmap of the required components to achieve a successful trauma outreach program. METHODS: This project describes the development and implementation of an educational outreach program from January 2016 to December 2020 that has grown from 27 facilities within one western state to 49 facilities across 14 different states. Program components measured include the number and attendance of trauma courses offered, including the Trauma Nursing Core Course (TNCC), Advanced Trauma Life Support (ATLS), Rural Trauma Team Development Course (RTTDC), the number of trauma meetings and webinars provided, total trauma center designation and reviews, total states reached, and total trauma center collaborations. RESULTS: From 2016 to 2020, the program more than doubled the number of TNCC and ATLS courses, maintained the number of RTTDC offered, and observed attendance rate increases of 33% and 11% for TNCC and ATLS courses, respectively. Outreach leadership attended 44 trauma meetings and educational webinars using virtual platform technology, nearly doubling the trauma center outreach with expansion across 14 states resulting in important changes in practice. CONCLUSION: With administrative support, effective leadership, and technology, outreach programs can serve as important resources for statewide trauma systems.

LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC.

BACKGROUND: Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 (Th1) products, such as IFNγ, TNFα, IL1-ß, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is a novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis and the hyper-inflammatory response associated with COVID-19. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release. METHODS: ELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα or IL-1ß relative potency were then employed to confirm the involvement of enriched pathways and TFs. RESULTS: LMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines (TNFα, IL-1ß, IL-12, CXCL9, CXCL10, and CXCL11) associated with pro-inflammatory M1/Th1 immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor (PPAR)γ and aryl hydrocarbon receptor (AhR), indicate these pathways are involved in the LMWF5A mechanisms of action by reducing LMWF5A drug potency as measured by TNFα and IL-1ß release. CONCLUSION: In this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ and AhR. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A acts through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.

Associations of Antithrombotic Timing and Regimen with Ischemic Stroke and Bleeding Complications in Blunt Cerebrovascular Injury.

BACKGROUND: Blunt cerebrovascular injuries (BCVIs) are associated with long-term neurological effects. The first-line treatment for BCVIs is antithrombotics, but consensus on the optimal choice and timing of treatment is lacking. METHODS: This was a retrospective study on patients aged at least 18 years admitted to 6 level 1 trauma centers between 1/1/2014 and 12/31/2017 with grade 1-4 BCVI and treated with antithrombotics. Differences in treatment practices were examined across the 6 centers. The primary outcome was ischemic stroke, and secondary outcomes were related to bleeding complications: blood transfusion and intracranial hemorrhage (ICH). Treatment characteristics examined were time to diagnosis and first computerized tomography angiography, time of total treatment course, time on each antithrombotic (anticoagulants, antiplatelets, combination), time from hospital arrival to antithrombotic initiation, and treatment interruption, i.e., treatment halted for a surgical procedure and restarted postoperatively. Chi-square, Fisher exact, Spearman's rank-order correlation, Wilcoxon rank-sum, Kruskal-Wallis, and Cox proportional hazards models with time-varying covariates were used to evaluate associations with the outcomes. RESULTS: A total of 189 patients with BCVI were included. The median (IQR) time from arrival to antithrombotic initiation was 27 (8-61) hours, and 28% of patients had treatment interrupted. The ischemic stroke rate was 7.5% (n = 14), with most strokes (64%, n = 9) occurring between arrival and treatment initiation. Treatment interruption was associated with ischemic stroke (75% of patients with stroke had an interruption versus 24% of patients with no stroke; P < .01). Time on anticoagulants was not associated with ischemic stroke (P = .78), transfusion (P = .43), or ICH (P = .96). Similarly, time on antiplatelets (P = .54, P = .65, P = .60) and time on combination therapy (P = .96, P = .38, P = .57) were not associated with these outcomes. CONCLUSIONS: The timing and consistency of antithrombotic administration are critical in preventing adverse outcomes in patients with BCVI. Most ischemic strokes in this study population occurred between arrival and antithrombotic initiation, representing events that may potentially be intervened upon by earlier treatment. Future studies should examine the safety of continuing treatment through surgical procedures.

Intravenous Low-Dose Ketamine Provides Greater Pain Control Compared to Fentanyl in a Civilian Prehospital Trauma System: A Propensity Matched Analysis.

Objective: A few studies report comparable analgesic efficacy between low-dose ketamine and opioids such as morphine or fentanyl; however, limited research has explored the safety and effectiveness of intravenous low-dose ketamine as a primary analgesic in a civilian prehospital setting. The objective of this study is to compare pain control between low-dose ketamine and fentanyl when administered intravenously (IV) for the indication of severe pain. Methods: This was a retrospective, observational review of prehospital adult patients (≥18 years) who presented with severe pain (numeric rating scale, 7-10) and were treated solely with either low-dose ketamine IV or fentanyl IV between January 1, 2014 and December 31, 2016. Propensity matched analysis was performed adjusting for all baseline variables with p ≤ 0.10 and for baseline pain score to match ketamine and fentanyl patients on a one-to-one ratio. The primary outcome was change in pain score from baseline to after treatment and evaluated with a paired t-test. Secondary outcomes were changes in vital signs and Glasgow coma scale (GCS) from baseline to after treatment, as well as incidence of clinically significant adverse events (AEs); AEs were followed from scene arrival through emergency department discharge. Results: Propensity matched analysis produced 79 matched pairs. Ketamine IV patients, receiving a mean (SD) dose of 0.3 (0.1) mg/kg, showed a significantly larger mean decrease in pain after treatment, compared to the fentanyl IV patients (-5.5 (3.1) vs. -2.5 (2.4), p < 0.001). A significantly greater proportion of patients receiving ketamine IV achieved at least a 50% reduction in pain compared to those receiving fentanyl IV (67% vs. 19%, p < 0.001), marking 52 ketamine IV patients as responders to treatment. Vital signs demonstrated a nonsignificant decrease in blood pressure, respiratory rate, heart rate, and GCS. No clinically significant AEs were reported for patients receiving ketamine IV. Conclusion: The significant reduction in pain, significantly high proportion of ketamine responders, and the lack of clinically significant AEs characterizing patients receiving low-dose ketamine IV compared to fentanyl IV, all provide further support for its use as an effective prehospital analgesic. Level of Evidence: Level III, therapeutic.

A Multicenter Performance Improvement Program Uses Rural Trauma Filters for Benchmarking: An Evaluation of the Findings.

Colorado requires Level III and IV trauma centers to conduct a formal performance improvement program (PI), but provides limited support for program development. Trauma program managers and coordinators in rural facilities rarely have experience in the development or management of a PI program. As a result, rural trauma centers often face challenges in evaluating trauma outcomes adequately. Through a multidisciplinary outreach program, our Trauma System worked with a group of rural trauma centers to identify and define seven specific PI filters based on key program elements of rural trauma centers. This retrospective observational project sought to develop and examine these PI filters so as to enhance the review and evaluation of patient care. The project included 924 trauma patients from eight Level IV and one Level III trauma centers. Seven PI filters were retrospectively collected and analyzed by quarter in 2016: prehospital managed airway for patients with a Glasgow Coma Scale (GCS) score of less than 9; adherence to trauma team activation criteria; evidence of physician team leader presence within 20 min of activation; patient with a GCS score less than 9 in the emergency department (ED): intubated in less than 20 min; ED length of stay (LOS) less than 4 hr from patient arrival to transfer; adherence to admission criteria; documentation of GCS on arrival, discharge, or with change of status. There was a significantly increasing compliance trend toward appropriate documentation of GCS (p trend < .001) and a significantly decreasing compliance trend for ED LOS of less than 4 hr (p trend = .04). Moving forward, these data will be used to develop compliance thresholds, to identify areas for improvement, and create corrective action plans as necessary.

Occurrence, Predictors, and Prognosis of Alcohol Withdrawal Syndrome and Delirium Tremens Following Traumatic Injury.

OBJECTIVES: We sought to determine occurrence, predictors, and prognosis of alcohol withdrawal syndrome and delirium tremens in patients with traumatic injury. DESIGN: Retrospective multicenter cohort study. SETTING: Three U.S. trauma centers. PATIENTS: Twenty-eight thousand one hundred one trauma patients admitted from 2010-2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measures included occurrence of alcohol withdrawal syndrome and delirium tremens, injury characteristics, risk factors for alcohol withdrawal syndrome, clinical outcomes, pharmacologic treatment for alcohol withdrawal syndrome, and Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar) scores. Alcohol withdrawal syndrome severity was defined by CIWA-Ar score as minimal (< 10), moderate (10-20), and severe (> 20). Alcohol withdrawal syndrome developed in 0.88% (n = 246), including 12% minimal, 36% moderate, and 53% severe. Alcohol withdrawal syndrome progressed to delirium tremens in 11%. Before adjustment, alcohol withdrawal syndrome severity was associated with injury severity, hypokalemia, baseline CIWA-Ar score, and established alcohol withdrawal syndrome risk factors. Logistic regression identified the following predictors of delirium tremens: baseline CIWA-Ar score greater than or equal to 10 (odds ratio, 6.05; p = 0.02) and age greater than or equal to 55 (odds ratio, 3.24; p = 0.03). In patients with severe alcohol withdrawal syndrome, severe head injury also predicted progression to delirium tremens (odds ratio, 6.08; p = 0.01), and hypokalemia was borderline significant (odds ratio, 3.23; p = 0.07). Clinical outcomes of hospital length of stay, ICU length of stay, and alcohol withdrawal syndrome complications differed significantly by alcohol withdrawal syndrome severity and were worse with more severe manifestations of alcohol withdrawal syndrome. Mortality also significantly differed by alcohol withdrawal syndrome severity but was only greater in patients who progressed to delirium tremens (11.1%; p = 0.02); otherwise, there were no differences in mortality by severity (4%, 4%, and 0% by minimal, moderate, and severe alcohol withdrawal syndrome). CONCLUSIONS: Trauma patients with alcohol withdrawal syndrome experience a high occurrence of delirium tremens that is associated with significant mortality. These data demonstrate the predictive ability of baseline CIWA-Ar score, age, and severe head injury for developing delirium tremens.

The low molecular weight fraction of human serum albumin upregulates production of 15d-PGJ2 in Peripheral Blood Mononuclear Cells.

Activation of the innate immune system involves a series of events designed to counteract the initial insult followed by the clearance of debris and promotion of healing. Aberrant regulation can lead to systemic inflammatory response syndrome, multiple organ failure, and chronic inflammation. A better understanding of the innate immune response may help manage complications while allowing for proper immune progression. In this study, the ability of several classes of anti-inflammatory drugs to affect LPS-induced cytokine and prostaglandin release from peripheral blood mononuclear cells (PBMC) was evaluated. PBMC were cultured in the presence of dexamethasone (DEX), ibuprofen (IBU), and the low molecular weight fraction of 5% albumin (LMWF5A) followed by stimulation with LPS. After 24 h, TNFα, PGE2, and 15d-PGJ2 release was determined by ELISA. Distinct immunomodulation patterns emerged following LPS stimulation of PBMC in the presence of said compounds. DEX, a steroid with strong immunosuppressive properties, reduced TNFα, PGE2, and 15d-PGJ2 release. IBU caused significant reduction in prostaglandin release while TNFα release was unchanged. An emerging biologic with known anti-inflammatory properties, LMWF5A, significantly reduced TNFα release while enhancing PGE2 and 15d-PGJ2 release. Incubating LMWF5A together with IBU negated this observed increased prostaglandin release without affecting the suppression of TNFα release. Additionally, LMWF5A caused an increase in COX-2 transcription and translation. LMWF5A exhibited a unique immune modulation pattern in PBMC, disparate from steroid or NSAID administration. This enhancement of prostaglandin release (specifically 15d-PGJ2), in conjunction with a decrease in TNFα release, suggests a switch that favors resolution and decreased inflammation.

Lights and Siren Transport and the Need for Hospital Intervention in Trauma Patients.

Emergent ambulance transportation is associated with increased risk of collision, injury, and death for EMS professionals, patients, and the general public. Time saved using lights and siren (L&S) is typically small, and often provides minimal clinical benefit. Our objective was to investigate the frequency of L&S transports, describe the precision of the decision to employ L&S to predict the need for a time critical hospital intervention (TCHI) within 15 minutes of hospital arrival, identify clinical predictors of a TCHI, and compare clinical outcomes in patients transported by Emergency Medical Services (EMS) with and without L&S in a trauma-specific population. EMS patient care reports and trauma registry data were retrospectively reviewed for trauma patients consecutively transported from the field by three EMS agencies to three trauma centers within urban and suburban settings over a two-year period. TCHIs were collaboratively developed by the study team. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were utilized to report the precision of the decision to employ L&S to predict the need of a TCHI. Univariate and multivariate analyses determined predictors of a TCHI and compared clinical outcomes. 2,091 patients were included in the study. Of the 19.8% of patients transported with L&S, 22.9% received a TCHI. The most common TCHI was airway or respiratory procedures (87.2% of all TCHI's). The sensitivity and specificity of L&S to predict the need for a TCHI was 87.2% (95% CI 79.4-92.8) and 84.0% (95% CI 82.2-85.5), respectively. PPV was 23.0% (95% CI 23.53-38.01); NPV was 99.2% (95% CI 98.6-99.6). L&S was predictive for the need for a TCHI (p < 0.001), as was abnormal Glasgow Coma Score (p < 0.001), abnormal systolic blood pressure and age (p < 0.05 for all). Among patients that received a TCHI, over a third that were transported with L&S (36.8%) expired, compared with two of 14 patients (14.3%) not transported L&S. EMS professionals in this study demonstrated a high ability to discern which trauma patients did not require L&S. Nevertheless, L&S transport resulted in a TCHI less than one quarter of the time, suggesting an opportunity for further reduction of L&S transports in trauma patients.

Anti-Inflammatory Activity in the Low Molecular Weight Fraction of Commercial Human Serum Albumin (LMWF5A).

The innate immune system is increasingly being recognized as a critical component in osteoarthritis (OA) pathophysiology. An ex vivo immunoassay utilizing human peripheral blood mononuclear cells (PBMC) was developed in order to assess the OA anti-inflammatory properties of the low molecular weight fraction (<5 kDa) of commercial human serum albumin (LMWF5A). PBMC from various donors were pre-incubated with LMWF5A before LPS stimulation. TNFα release was measured by ELISA in supernatants after an overnight incubation. A ≥ 30% decrease in TNFα release was observed. This anti-inflammatory effect is potentially useful in assessing potency of LMWF5A for the treatment of OA.

Developing, Implementing, and Evaluating a Nurse-Driven Rapid Reversal Protocol for Patients With Traumatic Intracerebral Hemorrhage in the Presence of Preinjury Warfarin.

Warfarin-related traumatic intracerebral hemorrhage (ICH) is often fatal, yet timely evaluation and treatment can improve outcomes. Our study describes the process of developing and implementing a protocol to guide the care of patients with traumatic brain injury (TBI) on preinjury warfarin developed by nurses across several service lines at our Level I trauma center over a 6-month period. Further, we evaluated its efficacy by examining records of adult patients with TBI on preinjury warfarin admitted 1 year before and after protocol implementation. Efficacy was defined as activation rates, receipt and time to head computed tomography (CT) scan and international normalization ratio (INR), and receipt and time to fresh frozen plasma (FFP) administration in patients with ICH with an INR more than 1.5, as per protocol. A subset analysis examined patients with and without an ICH. Outcomes were compared using univariate analyses. One hundred seventy-eight patients were included in the study; 90 (50.6%) were admitted before and 88 (49.4%) after implementation. After implementation, there were improvements in activation rates (34.4% vs. 65.9%; p < .001), the frequency of head CT scans (55.6% vs. 83.0%; p < .001), time to INR (24.0 min vs. 15.0 min; p < .05), and, for patients with ICH with an INR 1.5 or more, decreased time to FFP (157.0 vs. 90.5; p < .05). In conclusion, our protocol led to a more efficient process of care for patients with TBI on warfarin. We believe the implementation process, managed by a dedicated group of nurses across several service lines, substantially contributed to the success of the protocol.

Dipeptidyl peptidase IV activity in commercial solutions of human serum albumin.

Due to the heterogeneous nature of commercial human serum albumin (cHSA), other components, such as the protease dipeptidyl peptidase IV (DPP-IV), possibly contribute to the therapeutic effect of cHSA. Here, we provide evidence for the first time that DPP-IV activity contributes to the formation of aspartate-alanine diketopiperazine (DA-DKP), a known immunomodulatory molecule from the N terminus of human albumin. cHSA was assayed for DPP-IV activity using a specific DPP-IV substrate and inhibitor. DPP-IV activity was assayed at 37 and 60°C because cHSA solutions are pasteurized at 60°C. DPP-IV activity in cHSA was compared with other sources of albumin such as a recombinant albumin (rHSA). In addition, the production of DA-DKP was measured by negative electrospray ionization/liquid chromatography mass spectrometry (ESI(-)/LCMS). Significant levels of DPP-IV activity were present in cHSA. This activity was abolished using a specific DPP-IV inhibitor. Fully 70 to 80% DPP-IV activity remained at 60°C compared with the 37°C incubate. No DPP-IV activity was present in rHSA, suggesting that DPP-IV activity is present only in HSA produced using the Cohn fractionation process. The formation of DA-DKP at 60°C was observed with the DPP-IV inhibitor significantly decreasing this formation. DPP-IV activity in cHSA results in the production of DA-DKP, which could account for some of the clinical effects of cHSA.

Developing a rural trauma outreach program: the experience of a major health care network.

This study describes the process undertaken by a private health care network to develop and implement an outreach program for rural level III to V trauma centers. The program provided individualized trauma program support to 18 rural out-of-network facilities. A case study and participant satisfaction survey demonstrate the experiences of rural trauma nurse coordinators working with the program. The Trauma Outreach Program presents a solution to enhance the effectiveness of regional trauma systems, lift the burden on rural facilities, and improve care for the injured patient.

Whole Blood Resuscitation is Safe in Pediatric Trauma Patients: A Multicenter Study.

INTRODUCTION: Whole blood (WB) resuscitation has been associated with a mortality benefit in trauma patients. Several small series report the safe use of WB in the pediatric trauma population. We performed a subgroup analysis of the pediatric patients from a large prospective multicenter trial comparing patients receiving WB or blood component therapy (BCT) during trauma resuscitation. We hypothesized that WB resuscitation would be safe compared to BCT resuscitation in pediatric trauma patients. METHODS: This study included pediatric trauma patients (0-17 y), from ten level-I trauma centers, who received any blood transfusion during initial resuscitation. Patients were included in the WB group if they received at least one unit of WB during their resuscitation, and the BCT group was composed of patients receiving traditional blood product resuscitation. The primary outcome was in-hospital mortality with secondary outcomes being complications. Multivariate logistic regression was performed to assess for mortality and complications in those treated with WB vs BCT. RESULTS: Ninety patients, with both penetrating and blunt mechanisms of injury (MOI), were enrolled in the study (WB: 62 (69%), BCT: 28 (21%)). Whole blood patients were more likely to be male. There were no differences in age, MOI, shock index, or injury severity score between groups. On logistic regression, there was no difference in complications. Mortality was not different between the groups (P = .983). CONCLUSION: Our data suggest WB resuscitation is safe when compared to BCT resuscitation in the care of critically injured pediatric trauma patients.

Biphasic effect of danazol on human vascular endothelial cell permeability and f-actin cytoskeleton dynamics.

Breakdown of endothelial barrier function is a hallmark event across a variety of pathologies such as inflammation, cancer, and diabetes. It has also been appreciated that steroid hormones impart direct biological activity on endothelial cells at many levels. The purpose of this investigation was to explore the effect of the androgen-like steroid, danazol, on endothelial cell barrier function in vitro. Primary human endothelial cells exposed to 0.01-50 µM danazol were evaluated for changes in permeability. We found that danazol altered endothelial permeability in a biphasic manner in which nanomolar concentrations enhance barrier function while micromolar concentrations are detrimental. Monitoring of trans-endothelial electrical resistance demonstrated that these barrier enhancing effects were rapid (within 5 min) and lasted for over 24h. Analysis of intracellular f-actin organization showed that barrier enhancement also correlated with the formation of a submembranous cortical actin ring. Conversely, at higher danazol concentrations, contractile cell phenotypes were observed, represented by stress fiber formation. Competitive binding studies performed using steroid hormone receptor antagonists proved that this activity is the result of androgen and estrogen receptor ligation. These findings suggest that low dose danazol may provide a therapeutic window for diseases involving vascular leakage.

Development of a geriatric resuscitation protocol, utilization compliance, and outcomes.

Inconsistent application of trauma service resources and underevaluation of risk and resuscitation status in elderly trauma patients are problematic. We describe a geriatric protocol that includes initial lactate determination and trauma surgery admission. Protocol compliance rates were initial lactate determination, 67.9%; trauma service admission for overt or compensated (elevated lactate) shock, 73.6%; and trauma service consultation for nonshock patients, 67.8%. Implementation of this protocol resulted in a trend toward reduced mortality and reduced potentially preventable deaths.

Predictors of transfer from a remote trauma facility to an urban level I trauma center for blunt splenic injuries: a retrospective observational multicenter study.

BACKGROUND: The decision-making for admission versus emergent transfer of patients with blunt splenic injuries presenting to remote trauma centers with limited resources remains a challenge. Although splenectomy is standard for hemodynamically unstable patients, the specific criterion for non-operative management continues to be debated. Often, lower-level trauma centers do not have interventional radiology capabilities for splenic artery embolization, leading to transfer to a higher level of a care. Thus, the aim of this study was to identify specific characteristics of patients with blunt splenic injuries used for admittance or transfer at a remote trauma center. METHODS: A retrospective observational study was performed to examine the management of splenic injuries at a mountainous and remote Level III trauma center. Trauma patients ≥ 18 years who had a blunt splenic injury and initially received care at a Level III trauma center prior to admittance or transfer were included. Data were collected over 4.5 years (January 1, 2016 - June 1, 2020). Patients who were transferred out in > 24 h were excluded. Patient demographics, injury severity, spleen radiology findings, and clinical characteristics were compared by decision to admit or transfer to a higher level of care ≤ 24 h of injury. Results were analyzed using chi-square, Fisher's exact, or Wilcoxon tests. Multivariable logistic models were used to identify predictors of transfer. RESULTS: Of the 73 patients included with a blunt splenic injury, 48% were admitted and 52% were transferred to a Level I facility. Most patients were male (n = 58), were a median age of 26 (21-42) years old, most (n = 62) had no comorbidities, and 47 had been injured from a ski/snowboarding accident. Compared to admitted patients, transferred patients were significantly more likely to be female (13/38 vs. 3/36, p = 0.007), to have an abbreviated injury scale score ≥ 3 of the chest (31/38 vs. 7/35, p = 0.002), have a higher injury severity score (16 (16-22) vs. 13 (9-16), p = 0.008), and a splenic injury grade ≥ 3 (32/38 vs. 12/35, p < 0.001). After adjustment, splenic injury grade ≥ 3 was the only predictor of transfer (OR: 12.1, 95% CI: 3.9-37.3, p < 0.001). Of the 32 transfers with grades 3-5, 16 were observed, and 16 had an intervention. Compared to patients who were observed after transfer, significantly more who received an intervention had a blush on CT (1/16 vs. 7/16, p = 0.02) and a higher median spleen grade of 4 (3-5) vs. 3 (3-3.5), p = 0.01). CONCLUSIONS: Our data suggest that most patients transferred from a remote facility had a splenic injury grade ≥ 3, with concomitant injuries but were hemodynamically stable and were successfully managed non-operatively. Stratifying by spleen grade may assist remote trauma centers with refining transfer criteria for solid organ injuries.

AMP5A modulates Toll-like receptors 7 and 8 single-stranded RNA immune responses in PMA-differentiated THP-1 and PBMC.

Background: Dysregulation of antiviral immunity has been implicated in the progression of acute respiratory syndrome coronavirus 2 infection into severe cases of coronavirus disease of 2019 (COVID-19). Imbalances in the inflammatory response drive the overabundant production of pro-inflammatory cytokines and chemokines. The low molecular weight fraction of 5% human serum albumin commercial preparation (AMP5A) is a novel biologic drug currently under clinical investigation for the treatment of osteoarthritis and the hyperinflammatory response associated with COVID-19. This study aims to elucidate AMP5A effects following the activation of immune cells with agonists of Toll-like receptor (TLR) 7 and/or 8, which detect ssRNA viral sequences. Methods: CXCL10 ELISAs were used to evaluate the dynamics of myeloid cells activated with CL075 and CL307, agonists of TLR7/8 and TLR7, respectively. In addition, enrichment analysis of gene sets generated by ELISA arrays was utilized to gain insight into the biologic processes underlying the identified differentially expressed cytokine profiles. Finally, relative potency (REP) was employed to confirm the involvement of mechanisms of action paramount to AMP5A activity. Results: AMP5A inhibits the release of CXCL10 from both CL075- and CL307-activated PMA-differentiated THP-1 and peripheral blood mononuclear cells. Furthermore, AMP5A suppresses a distinct set of pro-inflammatory cytokines (including IL-1ß, IL-6, IL-12, and CXCL10) associated with COVID-19 and pro-inflammatory NF-κB activation. REP experiments using antagonists specific for the immunomodulatory transcription factors, peroxisome proliferator-activated receptor γ, and aryl hydrocarbon receptor, also indicate that these pathways are involved in the ability of AMP5A to inhibit CXCL10 release. Conclusion: Due to the biphasic course of COVID-19, therapeutic approaches that augment antiviral immunity may be more beneficial early in infection, whereas later interventions should focus on inflammation suppression. In this study, we show that AMP5A inhibits TLR 7/8 signaling in myeloid cells, resulting in a decrease in inflammatory mediators associated with hyperinflammation and autoimmunity. Furthermore, data demonstrating that AMP5A activates immunomodulatory transcription factors found to be protective in lung disease is provided. These findings suggest that the modes and mechanisms of action of AMP5A are well suited to treat conditions involving dysregulated TLR 7/8 activation.

C1 esterase inhibitor-mediated immunosuppression in COVID-19: Friend or foe?

From asymptomatic to severe, SARS-CoV-2, causative agent of COVID-19, elicits varying disease severities. Moreover, understanding innate and adaptive immune responses to SARS-CoV-2 is imperative since variants such as Omicron negatively impact adaptive antibody neutralization. Severe COVID-19 is, in part, associated with aberrant activation of complement and Factor XII (FXIIa), initiator of contact system activation. Paradoxically, a protein that inhibits the three known pathways of complement activation and FXIIa, C1 esterase inhibitor (C1-INH), is increased in COVID-19 patient plasma and is associated with disease severity. Here we review the role of C1-INH in the regulation of innate and adaptive immune responses. Additionally, we contextualize regulation of C1-INH and SERPING1, the gene encoding C1-INH, by other pathogens and SARS viruses and propose that viral proteins bind to C1-INH to inhibit its function in severe COVID-19. Finally, we review the current clinical trials and published results of exogenous C1-INH treatment in COVID-19 patients.