A proposed clinical coagulation score for research in trauma-induced coagulopathy.

BACKGROUND: Trauma-induced coagulopathy (TIC) has been the subject of intense study for greater than a century, and it is associated with high morbidity and mortality. The Trans-Agency Consortium for Trauma-Induced Coagulopathy, funded by the National Health Heart, Lung and Blood Institute, was tasked with developing a clinical TIC score, distinguishing between injury-induced bleeding from persistent bleeding due to TIC. We hypothesized that the Trans-Agency Consortium for Trauma-Induced Coagulopathy clinical TIC score would correlate with laboratory measures of coagulation, transfusion requirements, and mortality. METHODS: Trauma activation patients requiring a surgical procedure for hemostasis were scored in the operating room (OR) and in the first ICU day by the attending trauma surgeon. Conventional and viscoelastic (thrombelastography) coagulation assays, transfusion requirements, and mortality were correlated to the coagulation scores using the Cochran-Armitage trend test or linear regression for numerical variables. RESULTS: Increased OR TIC scores were significantly associated with abnormal conventional and viscoelastic measurements, including hyperfibrinolysis incidence, as well as with higher mortality and more frequent requirement for massive transfusion ( p < 0.0001 for all trends). Patients with OR TIC score greater than 3 were more than 31 times more likely to have an ICU TIC score greater than 3 (relative risk, 31.6; 95% confidence interval, 12.7-78.3; p < 0.0001). CONCLUSION: A clinically defined TIC score obtained in the OR reflected the requirement for massive transfusion and mortality in severely injured trauma patients and also correlated with abnormal coagulation assays. The OR TIC score should be validated in multicenter studies. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Empiric antifungals do not decrease the risk for organ space infection in patients with perforated peptic ulcer.

INTRODUCTION: Infection control in patients with perforated peptic ulcers (PPU) commonly includes empiric antifungals (AF). We investigated the variation in the use of empiric AF and explored the association between their use and the subsequent development of organ space infection (OSI). METHODS: This was a secondary analysis of a multicenter, case-control study of patients treated for PPU at nine institutions between 2011 and 2018. Microbiology and utilization of empiric AF, defined as AF administered within 24 hours from the index surgery, were recorded. Patients who received empiric AF were compared with those who did not. The primary outcome was OSI and secondary outcome was OSI with growth of Candida spp. A logistic regression was used to adjust for differences between the two cohorts. RESULTS: A total of 554 patients underwent a surgical procedure for PPU and had available timing of AF administration. The median age was 57 years and 61% were male. Laparoscopy was used in 24% and omental patch was the most common procedure performed (78%). Overall, 239 (43%) received empiric AF. There was a large variation in the use of empiric AF among participating centers, ranging from 25% to 68%. The overall incidence of OSI was 14% (77/554) and was similar for patients who did or did not receive empiric AF. The adjusted OR for development of OSI for patients who received empiric AF was 1.04 (95% CI 0.64 to 1.70), adjusted p=0.86. The overall incidence of OSI with growth of Candida spp was 5% and was similar for both groups (adjusted OR 1.29, 95% CI 0.59 to 2.84, adjusted p=0.53). CONCLUSION: For patients undergoing surgery for PPU, the use of empiric AF did not yield any significant clinical advantage in preventing OSI, even those due to Candida spp. Use of empiric AF in this setting is unnecessary. STUDY TYPE: Original article, case series. LEVEL OF EVIDENCE: III.

Strategies for successful implementation of resuscitative endovascular balloon occlusion of the aorta in an urban Level I trauma center.

BACKGROUND: The rationale for resuscitative endovascular balloon occlusion of the aorta (REBOA) is to control life-threatening subdiaphragmatic bleeding and facilitate resuscitation; however, incorporating this into the resuscitative practices of a trauma service remains challenging. The objective of this study is to describe the process of successful implementation of REBOA use in an academic urban Level I trauma center. All REBOA procedures from April 2014 through December 2019 were evaluated; REBOA was implemented after surgical faculty attended a required and internally developed Advanced Endovascular Strategies for Trauma Surgeons course. Success was defined by sustained early adoption rates. METHODS: An institutional protocol was published, and a REBOA supply cart was placed in the emergency department with posters attached to depict technical and procedural details. A focused professional practice evaluation was utilized for the first three REBOA procedures performed by each faculty member, leading to internal privileging. RESULTS: Resuscitative endovascular balloon occlusion of the aorta was performed in 97 patients by nine trauma surgeons, which is 1% of the total trauma admissions during this time. Each surgeon performed a median of 12 REBOAs (interquartile range, 5-14). Blunt (77/97, 81%) or penetrating abdominopelvic injuries (15/97, 15%) comprised the main injury mechanisms; 4% were placed for other reasons (4/97), including ruptured abdominal aortic aneurysms (n = 3) and preoperatively for a surgical oncologic resection (n = 1). Overall survival was 65% (63/97) with a steady early adoption trend that resulted in participation in a Department of Defense multicenter trial. CONCLUSION: Strategies for how departments adopt new procedures require clinical guidelines, a training program focused on competence, and a hospital education and privileging process for those acquiring new skills. LEVEL OF EVIDENCE: Therapeutic, level V.

Examining the Effect of Hypertonic Saline Administered for Reduction of Intracranial Hypertension on Coagulation.

BACKGROUND: Hypertonic saline (23.4%, HTS) bolus administration is common practice for refractory intracranial hypertension, but its effects on coagulation are unknown. We hypothesize that 23.4% HTS in whole blood results in progressive impairment of coagulation in vitro and in vivo in a murine model of traumatic brain injury (TBI). STUDY DESIGN: For the in vitro study, whole blood was collected from 10 healthy volunteers, and citrated native thrombelastography was performed with normal saline (0.9%, NS) and 23.4% HTS in serial dilutions (2.5%, 5%, and 10%). For the in vivo experiment, we assessed the effects of 23.4% HTS bolus vs NS on serial thrombelastography and tail-bleeding times in a TBI murine model (n = 10 rats with TBI and 10 controls). RESULTS: For the in vitro work, clinically relevant concentrations of HTS (2.5% dilution) shortened time to clot formation and increased clot strength (maximum amplitude) compared with control and NS. With higher HTS dosing (5% and 10% blood dilution), there was progressive prolongation of time to clot formation, decreased angle, and decreased maximum amplitude. In the in vivo study, there was no significant difference in thrombelastography measurements or tail-bleeding times after bolus administration of 23.4% HTS compared with NS at 2.5% blood volume. CONCLUSIONS: At clinically relevant dilutions of HTS, there is a paradoxical shortening of time to clot formation and increase in clot strength in vitro and no significant effects in a murine TBI model. However, with excess dilution, caution should be exercised when using serial HTS boluses in TBI patients at risk for trauma-induced coagulopathy.

Whole blood thrombin generation is distinct from plasma thrombin generation in healthy volunteers and after severe injury.

BACKGROUND: Plasma thrombin generation has been used to characterize trauma-induced coagulopathy, but description of whole blood thrombin generation is lacking. This study aimed to evaluate plasma and whole blood thrombin generation in healthy volunteers and trauma patients. We hypothesized that (1) plasma and whole blood thrombin generation are distinct, (2) whole blood thrombin generation is more pronounced in trauma patients than in healthy volunteers, and (3) thrombin generation correlates with clinical coagulation assays. METHODS: Blood was collected from healthy volunteers and trauma patients at a single, level-1 trauma center. Whole blood thrombin generation was assessed with a prototype point-of-care whole blood thrombin generation device, and plasma thrombin generation was measured with a calibrated automated thrombogram analogue. Plasma and whole blood thrombin generation were compared and correlated with international normalized ratio and thrombelastography. RESULTS: Overall, 10 healthy volunteers (average age 30, 50% men) were included and 58 trauma patients (average age 34, 76% men, 55% blunt mechanism, and with a median new injury severity score of 17) were included. Plasma and whole blood thrombin generation differed with more robust thrombin generation in plasma. Trauma patients had a significantly increased whole blood thrombin generation compared with healthy volunteers]. Plasma thrombin generation correlated with international normalized ratio, whereas whole blood thrombin generation did not correlate with thrombelastography. CONCLUSION: Plasma and whole blood thrombin generation are distinct, highlighting the need to perform standardized assays to better understand their correlation and to assess how whole blood thrombin generation confers differential outcomes in trauma.

Laparoscopic omental patch for perforated peptic ulcer disease reduces length of stay and complications, compared to open surgery: A SWSC multicenter study.

RCTs showed benefits in Lap repair of perforated peptic ulcer (PPU). The SWSC Multi-Center Trials Group sought to evaluate whether Lap omental patch repairs compared to Open improved outcomes in PPU in general practice. Data was collected from 9 SWSC Trial Group centers. Demographics, operative time, 30-day complications, length of stay and mortality were included. 461 PATIENTS: Open in 311(67%) patients, Lap in 132(28%) with 20(5%) patients converted from Lap to Open. Groups were similar at baseline. Significant variability was found between centers in their utilization of Lap (0-67%). Complications at 30 days were lower in Lap (18.5% vs. 27.5%, p < 0.05) as was unplanned re-operation (4.7% vs 14%, p < 0.05). Lap reduced LOS (6 vs 8 days, p < 0.001). Ileus was more in Lap (42% vs 18 p < 0.001) operative time was 14 min higher in Lap(p < 0.01) and admission to OR time was 4 h higher in Lap(<0.05). No significant difference readmission or mortality. Our results suggest Lap should be considered a first-line option in suitable PPU patients requiring omental patch repair in centers that have the capacity and resources 24/7.

Carotid Artery Entrapment by the Hyoid Bone-A Rare Cause of Recurrent Strokes in a Young Patient.

The search for etiology of stroke in a young patient may present a diagnostic challenge. In rare cases, chronic trauma to the carotid artery may be the cause of cerebral thromboembolic events. The hyoid bone lies in close proximity to the carotid artery bifurcation, and anatomic variants have been implicated in carotid compression, stenosis, dissection, and pseudoaneurysm. We report a case of recurrent strokes in a 32-year-old woman due to an elongated hyoid bone causing thrombus formation in her right internal carotid artery (ICA), resulting in recurrent embolic strokes confirmed on diffusion-weighted magnetic resonance imaging. Computed tomography angiography of the neck and head demonstrated the right hyoid bone was located between the ICA and external carotid artery (ECA), just above the carotid bifurcation, with residual nonocclusive thrombus in the right ICA. Carotid duplex ultrasonography confirmed that with the neck in neutral position, the hyoid was located between the ICA and ECA; however, with neck rotation, the hyoid slipped across the ICA and out of the bifurcation. There was no evidence of carotid stenosis. After an initial course of anticoagulation and antiplatelet therapy, resection of the greater cornu of the hyoid bone with release of the right ICA was performed. One year postoperatively, the patient had complete return of neurologic function and had no further neurologic events. Hyoid bone entrapment of the carotid artery is a rare etiology of thromboembolic stroke caused by repetitive local trauma. The diagnosis can be confirmed by carotid duplex with provocative maneuvers. Partial hyoid resection is a safe and effective treatment to relieve recurrent symptoms. Hyoid bone entrapment may be an important and under-recognized cause of stroke in young adults.

Inferior Vena Cava Filter Resulting in Perforation and Massive Retroperitoneal Hematoma Presenting as Acute Onset of Lower Extremity Weakness.

Perforation of inferior vena cava (IVC) filter struts is a common incidental finding on postoperative computed tomography (CT) scans that is not associated with bleeding or major complications. However, in rare circumstances, it can be associated with hemorrhage requiring immediate removal. We present a case of a 62-year-old man who developed abdominal pain and right lower extremity weakness 2 weeks after treatment of a pulmonary embolism with IVC filter placement and anticoagulation. A CT scan revealed a large right-sided retroperitoneal hematoma with active extravasation from the IVC filter struts that had perforated the IVC wall. He underwent a hybrid operation with endovascular retrieval of the IVC filter and concomitant IVC primary repair combined with evacuation of the hematoma, causing nerve compression. Postoperatively, he regained normal sensory and motor function. Perforation of IVC filter struts is usually asymptomatic, but in rare circumstances, it can cause hemorrhage requiring immediate removal and IVC repair. Surgical intervention is indicated in the setting of a large hematoma with nerve or vessel compression and may require a combined endovascular and open approach.

Fourth Time Redo Common Femoral Vein Reconstruction with a Novel Hybrid Technique.

BACKGROUND: Iliofemoral vein thrombosis can lead to debilitating edema and venous claudication that significantly worsens quality of life, especially in young active individuals. Venous reconstruction becomes increasingly complex and has worsening patency with subsequent revisions so preoperative planning is critical to success. METHODS: We report a case of a 54-year-old man in active military service with profoundly symptomatic leg swelling after failure of 3 previous common femoral vein (CFV) reconstructions. The CFV and distal external iliac vein were thrombosed up to a few centimeters above the inguinal ligament. Direct proximal control would have required a retroperitoneal or transabdominal incision. However, a hybrid approach utilizing through-wire access, remote balloon control of the external iliac vein, cryopreserved vein graft, stent graft, and arteriovenous fistula was able to address the factors (graft size, external compression, adequate flow) contributing to his previous graft failures with a novel, less invasive approach. RESULTS: At 1-year follow-up, he was asymptomatic and the graft remained patent with normal vascular duplex studies. His leg swelling subsided and he was able to return to his previous physical activity level. CONCLUSIONS: A hybrid approach to complex venous reconstruction can provide a minimally invasive and durable alternative to more invasive procedures and alleviate mechanical causes of early graft failure.

p62 expression and autophagy in αB-crystallin R120G mutant knock-in mouse model of hereditary cataract.

The formation of cataracts is associated with the accumulation of protein aggregates in the ocular lens, suggesting that defective protein degradation plays a role in cataract pathogenesis. Accumulation of the p62 protein has recently been identified as a marker for impaired autophagy in a variety of tissues; however, little information exists on its expression in the ocular lens and in cataracts. In the present study we examined the expression of p62 in the mouse lens and compared its expression in wild-type lenses with that in lenses from knock-in mice with an arginine to glycine mutation in αB-crystallin (αB-R120G) that is known to cause human hereditary cataract. Immunohistochemical, immunoblotting, and transmission electron microscopic analyses of wild type and αB-R120G mutant mice were performed. To assess the effect of increased protein aggregation on autophagy, immunohistochemical staining was performed with an anti-p62 antibody, revealing the presence of p62-positive punctate staining in a band of denucleated cortical fiber cells. The number and size of p62 puncta were significantly greater in αB-R120G homozygous mutant lenses than in wild type and heterozygous mutant lenses. p62 staining was also abundant in lens epithelial cells and was concentrated around the nuclear membrane. Double-membraned structures similar to autophagosomes containing cellular cytoplasmic content were detected in lens epithelial cells by transmission electron microscopy. The autophagosomes in lens epithelial cells from αB-R120G homozygous mutant mice were larger than those in wild type mice. Double-membraned structures that are probably autophagosomes were also detected in cortical fiber cells and were more abundant in the αB-R120G homozygous mutant lens than the wild type lens. This study demonstrates p62 distribution as speckles in the lens fiber cells, altered levels of p62 expression, and the presence of autophagosomes in the ocular lens of αB-R120G mutant mice. We propose that autophagy is inhibited in the αB-R120G mutant lenses because of a defect in protein degradation after autophagosome formation. Further work is necessary to determine the relationship between αB-crystallin function, autophagy, and cataract formation.

Overexpression of amyloid-ß protein precursor induces mitochondrial oxidative stress and activates the intrinsic apoptotic cascade.

Aberrant processing of amyloid-ß protein precursor (AßPP) into amyloid-ß (Aß) fragments underlies the formation of senile plaques in Alzheimer's disease (AD). Moreover, Aß fragments, particularly Aß(42), exert direct toxic effects within neurons including the induction of mitochondrial oxidative stress (MOS). Interestingly, individuals with Down syndrome (DS) frequently develop early onset AD as a major co-morbid phenotype. One hypothesis for AD associated with DS involves the overexpression of wild type (WT) AßPP protein, due to its location on chromosome 21. However, the mechanism by which the overexpression of WT AßPP might trigger MOS and induce cell death is presently unclear. Here we show that transient overexpression of DsRed2-tagged AßPP (WT) in CHO cells induces caspase-3 activation and nuclear fragmentation indicative of apoptosis. AßPP localizes to the mitochondrial fraction of transfected CHO cells and induces glutathione-sensitive opening of the mitochondrial permeability transition pore (mPTP) and cytochrome c release. MOS and intrinsic apoptosis induced by AßPP are significantly inhibited by co-expression of Bcl-2 or treatment with either glutathione or a pan-caspase inhibitor. The mPTP inhibitor, cyclosporin A, also significantly attenuates AßPP-induced apoptosis. AßPP-induced apoptosis is unaffected by a ß-secretase inhibitor and is independent of detectable Aß(42); however, a γ-secretase inhibitor significantly protects against AßPP overexpression, suggesting a possible role of the AßPP intracellular domain in cell death. These data indicate that overexpression of WT AßPP is sufficient to induce MOS and intrinsic apoptosis, suggesting a novel pro-oxidant role for AßPP at mitochondria which may be relevant in AD and DS disease pathologies.

T cell hybridomas to study MHC-II restricted B-cell receptor-mediated antigen presentation by human B cells.

MHC-II antigen presentation by B cells is essential in order for B cells to receive optimal costimulation from helper CD4+ T cells. This process is facilitated and focused through the extremely efficient uptake, processing, and presentation of antigen recognized by an individual B cell's unique B-cell receptor (BCR). The investigation of human B-cell antigen presentation has been limited by the varied specificity of BCR found in the mixed populations of B cells in vivo. As a result, there is no readily available method to measure BCR-mediated antigen presentation in this heterogeneous population of B cells. We have overcome this limitation by developing HLA-DR-restricted T-cell lines capable of recognizing a specific antigen taken up via the BCR and presented by the mixed B-cell population through this physiologically relevant mechanism. BCR-mediated presentation was enhanced >4 logs compared to presentation by B cells taking up the antigen through nonspecific mechanisms. The studies presented here characterize T-cell hybridoma lines developed for HLA-DRB1*0101+ and HLA-DRB1*1501+ B cells, but clones could be generated for other HLA-DR types using the methods described. These hybridomas have potential applications including study of the mechanisms of BCR-mediated enhancement of presentation, determination of adjuvant effects on presentation, and optimization of vaccine antigen preparations. Therefore, these T-cell lines could significantly facilitate the study of BCR-mediated antigen presentation required by T helper cell-dependent vaccines in humans.