Dose-Related Effectiveness of Andexanet Alfa for Reversal of Apixaban Anticoagulation in a Porcine Polytrauma Model.

BACKGROUND: Andexanet alfa (andexanet) is a reversal agent for use in patients with life-threatening or uncontrolled bleeding treated with oral factor Xa (FXa) inhibitors. There are limited data on the dose-response relationship of andexanet and FXa inhibitor-related bleeding. OBJECTIVE: The aim of this study was to assess the dose-related effectiveness of andexanet in reducing blood loss, improving survival, and reversing apixaban anticoagulation in a porcine polytrauma model. METHODS: Apixaban was given orally to 40 male pigs for 3 days at a dose of 20 mg/d. On day 3, following bilateral femur fractures and blunt liver injury, animals (n = 8/group) received andexanet (250-mg bolus, 250-mg bolus + 300-mg 2-hour infusion, 500-mg bolus, or 500-mg bolus + 600-mg 2-hour infusion) or vehicle (control). Total blood loss was the primary endpoint. Coagulation parameters were assessed for 300 minutes or until death. Data were analyzed with a mixed-model analysis of variance. RESULTS: Administration of 250-mg bolus + 300-mg infusion, andexanet 500-mg bolus, and 500-mg bolus + 600-mg infusion significantly decreased total blood loss by 37, 58, and 61%, respectively (all p < 0.0001), with 100% survival. Andexanet 250-mg bolus was ineffective in reducing total blood loss (6%) and mortality (63% survival) versus controls. Andexanet 500-mg bolus ± infusion neutralized anti-FXa activity to less than 50 ng/mL. Andexanet neutralization of thrombin generation and thromboelastometry parameters was dose and infusion time dependent. CONCLUSION: In a porcine polytrauma model with major bleeding on apixaban, andexanet dose dependently decreased anti-FXa activity. Lower anti-FXa levels (<50 ng/mL) with andexanet 500-mg bolus ± infusion were correlated with 60% less blood loss and 100% survival versus controls.

Resultados del Registro Nacional de Politraumatismos español ¿Dónde estamos y a dónde nos dirigimos? / Results of the Spanish National Polytrauma Registry. Where are we and where are we heading?

Introducción: En 2017 se emprendió el Registro Nacional de Politraumatismos (RNP) a nivel estatal español, cuya finalidad residía en mejorar la calidad de la atención al paciente politraumatizado grave y evaluar el uso de recursos y estrategias de tratamiento. El objetivo de este trabajo es presentar los datos recogidos en el RNP hasta la actualidad. Métodos: Estudio observacional retrospectivo a partir de los datos recogidos prospectivamente en el RNP. Se incluyen pacientes mayores de 14 años, con ISS≥15 o mecanismo de trauma penetrante, atendidos en 17 hospitales de tercer nivel de España. Resultados: Del 1/1/17 al 1/1/22 se han registrado un total de 2.069 pacientes politraumatizados. El 76,4% son varones; edad media: 45 años; ISS medio: 22,8 y mortalidad: 10,2%. El mecanismo de lesión más frecuente es el cerrado (80%) con mayor incidencia de accidentes de moto (23%). Un 12% de los pacientes sufren un traumatismo penetrante, por arma blanca en el 84%. Un 16% de los pacientes ingresa hemodinámicamente inestable en el hospital. Activando el protocolo de transfusión masiva en el 14% de los pacientes e interviniendo quirúrgicamente a un 53%. La estancia hospitalaria mediana es de 11 días. Precisando ingreso en la UCI un 73,4% (estancia media: 5 días). Conclusiones: Los pacientes politraumatizados registrados en el RNP son mayoritariamente varones de mediana edad, que sufren traumatismos cerrados y presentan una elevada incidencia de lesiones torácicas. La detección y el tratamiento dirigido de este tipo de lesiones probablemente permitirá mejorar la calidad asistencial del politraumatizado en nuestro medio. (AU)

Introduction: In 2017 the Spanish National Polytrauma Registry (SNPR) was initiated in Spain, its goal was to improve the quality of severe trauma management and evaluate the use of resources and treatment strategies. The objective of this study is to present the information obtained with the SNPR since it was initiated. Methods: Observational study with prospective data collection from the SNPR. Trauma patients included are older than 14 yeas, with ISS ≥ 15 or penetrating mechanism. In total 17 hospitals from Spain have participated. Results: From 1/1/17 to 1/1/22, 2069 trauma patients were registered. The majority were men (76.4%); mean age: 45 years; mean ISS: 22.8 and mortality: 10.2%. The most common mechanism of injury was blunt trauma (80%), being motorbike accident the most frequent (23%). Penetrating trauma is presented in 12% of patients, being stab wound the most common (84%). Sixteen percent of patients are hemodynamically unstable on hospital arrival. Massive transfusion protocol is activated in 14% of patients and 53% are operated. Median hospital stay is 11 days. There is a 73.4% of patients who need intensive care unit (ICU) admission, with a median ICU stay of 5 days. Conclusions: Trauma patients registered in the SNPR are predominantly middle-aged males who experience blunt trauma with a high incidence of thoracic injuries. Early and addressed detection of these kind of injuries would probably improve trauma quality of care in our environment. (AU)

EFFECTS OF TRANEXAMIC ACID ON NEUROPATHOLOGY, ELECTROENCEPHALOGRAPHY, AND CEREBRAL FIBRIN DEPOSITION IN A RAT MODEL OF POLYTRAUMA WITH CONCOMITANT PENETRATING TRAUMATIC BRAIN INJURY.

ABSTRACT: Several studies have demonstrated the clinical utility of tranexamic acid (TXA) for use in trauma patients presenting with significant hemorrhage. Tranexamic acid is an antifibrinolytic that inhibits plasminogen activation, and plasmin activity has been shown to mitigate blood loss and reduce all-cause mortality in the absence of adverse vascular occlusive events. Recent clinical developments indicate TXA is safe to use in patients with concomitant traumatic brain injury (TBI); however, the prehospital effects are not well understood. Importantly, TXA has been associated with seizure activity. Therefore, this study sought to evaluate the effects of early administration of TXA on neurological recovery and electroencephalogram (EEG) abnormalities following penetrating TBI with concomitant hypoxemia and hemorrhagic shock. We hypothesized that early administration of TXA will provide hemodynamic stabilization and reduce intracerebral hemorrhage, which will result in improved neurological function. To test this hypothesis, Sprague-Dawley rats received a unilateral, frontal penetrating ballistic-like brain injury by inserting a probe into the frontal cortex of the anesthetized rat. Five minutes following brain injury, animals underwent 30 min of respiratory distress and 30 min of hemorrhage. Upon completion of the hemorrhage phase, animals received the initial dose of drug intravenously over 10 min after which the prehospital phase was initiated. During the prehospital phase, animals received autologous shed whole blood as needed to maintain a MAP of 65 mm Hg. After 90 min, "in-hospital" resuscitation was performed by administering the remaining shed whole blood providing 100% oxygen for 15 min. Upon recovery from surgery, animals were administered their second dose of vehicle or TXA intravenously over 8 h. Tranexamic acid induced an early improvement in neurologic deficit, which was statistically significant compared with vehicle at 24, 48, and 72 h at three doses tested. Analysis of cerebral hemoglobin content and intracerebral lesion progression revealed 100 mg/kg provided the optimal effects for improvement of neuropathology and was continued for determination of adverse treatment effects. We observed no exacerbation of cerebral thrombosis, but TXA treatment caused an increased risk of EEG abnormalities. These results suggest that TXA following polytrauma with concomitant brain injury may provide mild neuroprotective effects by preventing lesion progression, but this may be associated with an increased risk of abnormal EEG patterns. This risk may be associated with TXA inhibition of glycine receptors and may warrant additional considerations during the use of TXA in patients with severe TBI.

5-HT3 SEROTONIN RECEPTOR BLOCKERS FOR INTENSIVE THERAPY OF TRAUMATIC DISEASE IN PATIENTS WITH MULTIPLE TRAUMA.

OBJECTIVE: The aim: To find the most rational choice of drugs that have anti-emetic effect in patients with polytrauma in acute and early periods. PATIENTS AND METHODS: Materials and methods: We examined 82 patients with polytrauma, 62 men and 20 women. The age of patients ranged from 19 to 50 years. Patients were divided into the main and control group with 36 and 46 people respectively, who did not differ significantly by sex, age, anthropometric data, the nature and severity of injuries, and the time from injury to admission to hospital. RESULTS: Results: Full antiemetic effect was achieved in 72.4% of patients, where metoclopramide was used. Сomplete antiemetic effect was achieved in 96.3% of patients, where sturgeon was used. Decrease of peristaltic activity does not increase postoperative intestinal paresis, and also prevents irritable bowel syndrome and diarrhea caused by dysbacteriosis on the background of antibiotic therapy. Anxiolytic effect without sedative effect and impairment of motor coordination, decrease of the somatic and psychopathological symptoms intensity in alcohol-toxic withdrawal syndrome contributes to the correct interpretation of the traumatic disease. CONCLUSION: Conclusions: Use of drugs with antiemetic effect is an important part of the complex of traumatic disease treatment in patients with polytrauma. The use of osetron is rational in patients with polytrauma with cranio-abdominal injuries.

The effect of prehospital tranexamic acid on outcome in polytrauma patients with associated severe brain injury.

INTRODUCTION: Tranexamic acid (TXA) has shown to be beneficial in selected patients with hemorrhagic shock. Recently, TXA has gained interest in isolated traumatic brain injury (TBI) patients with variable results. There are limited data on TXA in polytrauma with associated TBI. This study investigated the role of TXA in severely injured patients with associated severe TBI. METHODS: A 7.5-year prospective cohort study was performed to investigate the relation between prehospital TXA and mortality in consecutive trauma patients with associated severe TBI (Abbreviated Injury Scale (AIS)head ≥ 3) admitted to a Level-1 Trauma Center ICU. Indication for prehospital TXA administration was (suspicion of) hemorrhagic shock, and/or systolic blood pressure (SBP) ≤ 90 mmHg. Demographics, data on physiology, resuscitation, and outcomes were prospectively collected. RESULTS: Two hundred thirty-four patients (67% males) with median age of 49 years and ISS 33 (98% blunt injuries) were included. Thirteen patients (6%) developed thromboembolic complications; mortality rate was 24%. Fifty-one percent of patients received prehospital TXA. TXA patients were younger, had more deranged physiology on arrival, and received more crystalloids and blood products ≤ 24 h. There was, however, no difference in overall outcome between TXA patients and no-TXA patients. CONCLUSIONS: Despite having a more deranged physiology TXA patients had similar outcome compared to no-TXA patients who were much older. Thromboembolic complication rate was low. Prehospital tranexamic acid has no evident effect on outcome in polytrauma patients with associated critical brain injury.

Reversing Rivaroxaban Anticoagulation as Part of a Multimodal Hemostatic Intervention in a Polytrauma Animal Model.

BACKGROUND: Life-threatening bleeding requires prompt reversal of the anticoagulant effects of factor Xa inhibitors. This study investigated the effectiveness of four-factor prothrombin complex concentrate in treating trauma-related hemorrhage with rivaroxaban-anticoagulation in a pig polytrauma model. This study also tested the hypothesis that the combined use of a low dose of prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate could improve its subtherapeutic effects. METHODS: Trauma (blunt liver injury and bilateral femur fractures) was induced in 48 anesthetized male pigs after 30 min of rivaroxaban infusion (1 mg/kg). Animals in the first part of the study received prothrombin complex concentrate (12.5, 25, and 50 U/kg). In the second part, animals were treated with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid or plus tranexamic acid and fibrinogen concentrate. The primary endpoint was total blood loss postinjury. The secondary endpoints (panel of coagulation parameters and thrombin generation) were monitored for 240 min posttrauma or until death. RESULTS: The first part of the study showed that blood loss was significantly lower in the 25 U/kg prothrombin complex concentrate (1,541 ± 269 ml) and 50 U/kg prothrombin complex concentrate (1,464 ± 108 ml) compared with control (3,313 ± 634 ml), and 12.5 U/kg prothrombin complex concentrate (2,671 ± 334 ml, all P < 0.0001). In the second part of the study, blood loss was significantly less in the 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate (1,836 ± 556 ml, P < 0.001) compared with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid (2,910 ± 856 ml), and there were no early deaths in the 25 U/kg prothrombin complex concentrate, 50 U/kg prothrombin complex concentrate, and 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate groups. Histopathologic analyses postmortem showed no adverse events. CONCLUSIONS: Prothrombin complex concentrate effectively reduced blood loss, restored hemostasis, and balanced thrombin generation. A multimodal hemostatic approach using tranexamic acid plus fibrinogen concentrate enhanced the effect of low doses of prothrombin complex concentrate, potentially reducing the prothrombin complex concentrate doses required for effective bleeding control.

Incidence and Nature of Lower-Limb Deep Vein Thrombosis in Patients with Polytrauma on Thromboprophylaxis: A Prospective Cohort Study.

PURPOSE: Deep vein thrombosis (DVT) is common among the severely injured and may lead to pulmonary embolism (PE), which can be life threatening. Thromboprophylaxis may reduce the incidence of venous thromboembolism (VTE); it does not guarantee complete protection. This study's primary aim was to determine the incidence and nature of lower-limb DVT in polytrauma patients taking prophylaxis. The secondary objective was to assess the incidence of DVT-related complications, including the development of PE and death. PATIENTS AND METHODS: This prospective observational study included patients age 18 years or older who presented with polytrauma directly from the scene and were admitted into the trauma unit between March 1, 2020 and August 31, 2020. All patients underwent lower-limb ultrasound during their hospital course to diagnose DVT. RESULTS: A total of 169 patients underwent extremity Doppler ultrasound to detect DVT. Of these, 69 patients (40.8%) were considered at the highest-risk for VTE development. For VTE prophylaxis, 115 patients (68%) received pharmacologic agents, and 54 patients (32%) had intermittent pneumatic compression on admission. Three patients (1.8%) developed DVT despite prophylaxis. Four patients (2.4%) developed PE during the index presentation and were diagnosed between days 3 and 13 after injury. Early DVT was not detected in any patients with diagnosed PE. Overall, nine patients (5.33%) died, but no in-hospital deaths were related to DVT and/or PE. CONCLUSION: The incidence of DVT in polytrauma patients remains low in our small series, perhaps because of the mandatory VTE risk assessment for all hospitalized patients and the early initiation of prophylaxis. Using a trauma center registry to measure DVT and PE incidence regularly is recommended to improve trauma care quality.

[Administration of Anabolic Steroids in Combination with Vitamin D in the Early Stage of Treatment of Polytrauma Patients - a Dead End?] / Aplikace anabolických steroidu s vitaminem D v casné fázi lécby polytraumatizovaných pacientu ­ slepá ulicka?

PURPOSE OF THE STUDY Persistent catabolism is one of the main causes of delayed healing in polytrauma patients. The purpose of this study is to verify the effect of early administration of an anabolic steroid in combination with vitamin D on the process of bone healing in polytrauma patients. MATERIAL AND METHODS In this prospective study, the patients with a serious trauma were divided into two groups (a control group and a treatment group), with the treatment group being treated with nandrolone decanoate, an anabolic steroid in combination with vitamin D. In all the patients, bone metabolism markers and sex hormone levels (men only) were monitored through lab testing for the period of 70 days and the results of both the groups were subsequently compared. RESULTS The study included a total of 64 patients, 32 in the control group and 32 in the treatment group. The differences between the groups in gender (p = 0.387) as well as in the age of patients (p = 0.436) were statistically non-significant. There was a significant difference in the Injury Severity Score (48 in the treatment group as against 41 in the control group, p = 0.022). Even though this difference was statistically significant, it cannot be considered clinically significant since all the patients met the major trauma criteria. No positive effect of this treatment on bone metabolism parameters was established; on the very contrary, the only statistically significant changes were observed in the control group. To be specific, in levels of one of the bone formation markers, bone alkaline phosphatase on Day 7 after the injury (an increased level in the control group; p = 0.002) and in one of the bone resorption markers (bone acid phosphatase) on Day 70 after the injury (an increased level in the treatment group; p = 0.042). In the treatment group, 70 days after the injury a higher 25(OH)vitamin D level (p < 0.001) was reported and starting from Day 7 in men in the treatment group a significantly lower testosterone level and free testosterone level were observed. The level of androgenic hormones dramatically dropped in both the groups during the first days after the trauma, the dynamics of its normalization was faster in patients in the control group than in the treatment group. DISCUSSION The administration of nandrolone decanoate, an anabolic steroid, in combination with vitamin D did not produce the expected effect, i.e. an improvement in bone healing markers in polytrauma patients. One would expect that in polytrauma patients with a bone fracture or fractures during bone healing higher levels of all the markers of bone resorption as well as bone formation will persist. Similar increases in bone metabolism levels, however, were observed also in patients with injuries in other somatic regions. This indicates the importance of bone tissue involvement in the overall response of the organism to polytrauma. A faster normalization of the levels of testosterone, dihydrotestosterone and free testosterone in the control group compared to the treatment group corresponds with the supplemental effect of anabolic steroids and reduced production of these hormones as a feedback to hypothalamic-pituitary-adrenal axis. CONCLUSIONS In the follow-up period, the positive effect of anabolic steroid and vitamin D administration on bone metabolism in polytrauma patients was not confirmed. Key words: polytrauma, anabolic steroids, vitamin D, bone metabolism.

Bosutinib reduces endothelial permeability and organ failure in a rat polytrauma transfusion model.

BACKGROUND: Trauma-induced shock is associated with endothelial dysfunction. We examined whether the tyrosine kinase inhibitor bosutinib as an adjunct therapy to a balanced blood component resuscitation strategy reduces trauma-induced endothelial permeability, thereby improving shock reversal and limiting transfusion requirements and organ failure in a rat polytrauma transfusion model. METHODS: Male Sprague-Dawley rats (n=13 per group) were traumatised and exsanguinated until a MAP of 40 mm Hg was reached, then randomised to two groups: red blood cells, plasma and platelets in a 1:1:1 ratio with either bosutinib or vehicle. Controls were randomised to sham (median laparotomy, no trauma) with bosutinib or vehicle. Organs were harvested for histology and wet/dry (W/D) weight ratio. RESULTS: Traumatic injury resulted in shock, with higher lactate levels compared with controls. In trauma-induced shock, the resuscitation volume needed to obtain a MAP of 60 mm Hg was lower in bosutinib-treated animals (2.8 [2.7-3.2] ml kg-1) compared with vehicle (6.1 [5.1-7.2] ml kg-1, P<0.001). Lactate levels in the bosutinib group were 2.9 [1.7-4.8] mM compared with 6.2 [3.1-14.1] mM in the vehicle group (P=0.06). Bosutinib compared with vehicle reduced lung vascular leakage (W/D ratio of 5.1 [4.6-5.3] vs 5.7 [5.4-6.0] (P=0.046) and lung injury scores (P=0.027). CONCLUSIONS: Bosutinib as an adjunct therapy to a balanced transfusion strategy reduced resuscitation volume, improved shock reversal, and reduced vascular leak and organ injury in a rat polytrauma model.

Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial.

BACKGROUND: The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. METHODS: The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. RESULTS: There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58-0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69-1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83-1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70-0.87) and death within 28 days (RR 0.88, 95% CI 0.82-0.94). CONCLUSIONS: Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. TRIAL REGISTRATION: ISRCTN15088122 , registered on 19 July 2011; NCT01402882 , registered on 26 July 2011.

Trichosporon Asahii fungaemia in an immunocompetent polytrauma patient who received multiple antibiotics.

Trichosporon asahii is a yeast-like fungus that is emerging as an important cause of invasive infections in tertiary medical centres. A 58-year-old Chinese man with no known medical illnesses presented with liver lacerations and multiple fractures following an alleged 12-foot fall at a construction site. The gravity of his injuries and poor haemodynamic status necessitated an intensive care unit (ICU) admission, during which several febrile episodes were detected and multiple antibiotics were administered. After being in the ICU for at least two weeks, a urease-positive yeast was isolated from the patient's blood. The yeast formed dry, fuzzy and wrinkled white colonies on Sabouraud dextrose agar following prolonged incubation, and produced blastoconidia, true hyphae, pseudohyphae and arthroconidia on slide culture. It was identified biochemically by the ID 32 C kit as T. asahii. The yeast had elevated minimal inhibitory concentration (MIC) values to fluconazole, amphotericin B, flucytosine and all echinocandins tested. In view of this, the patient was treated with voriconazole and was successfully transferred to the general medical ward.

Utilization of whole body computed tomography in polytrauma patients.

OBJECTIVE: To determine the safety, feasibility, and utility of whole body computed tomography (WBCT) in polytrauma patients. A second objective was to describe the utilization of the VetMouse Trap for sedated WBCT in polytrauma patients. METHODS: A prospective, observational study in a high-volume private practice. Any cat or dog weighing <20 kg that presented to the emergency department following a polytrauma was eligible. Patients were given analgesia and sedation prior to placement in the VetMouse Trap. A WBCT was then performed. RESULTS: A total of 16 patients (8 dogs and 8 cats) met inclusion criteria. All patients presented with blunt trauma; 3 also had evidence of penetrating wounds. Five (31.25%) patients met inclusion criteria for WBCT based on their neurological evaluation. Five (31.5%) were non-ambulatory with suspicion of orthopedic injury, and 37.5% met additional criteria for WBCT. The most common areas of injury were head (43.7%), lungs (25%), and pelvis (25%). Four patients (25%) had evidence of cavitary effusion that was not seen on focused assessment using sonography for trauma (FAST) scan. No patient had any adverse events during the CT. CONCLUSION: This study demonstrated successful WBCT imaging of the sedated small animal polytrauma patient with the VetMouse Trap.

Ácido tranexámico en el paciente politraumatizado: ¿bueno, bonito y barato? / Tranexamic acid in patients with multiple injuries: good, elegant, and cheap?

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Platelet-derived extracellular vesicles released after trauma promote hemostasis and contribute to DVT in mice.

BACKGROUND: Traumatic injury can lead to dysregulation of the normal clotting system, resulting in hemorrhagic and thrombotic complications. Platelet activation is robust following traumatic injury and one process of platelet activation is to release of extracellular vesicles (PEV) that carry heterogenous cargo loads and surface ligands. OBJECTIVES: We sought to investigate and characterize the release and function of PEVs generated following traumatic injury. METHODS: PEV content and quantity in circulation following trauma in humans and mice was measured using flow cytometry, size exclusion chromatography, and nanoparticle tracking analysis. PEVs were isolated from circulation and the effects on thrombin generation, bleeding time, hemorrhage control, and thrombus formation were determined. Finally, the effect of hydroxychloroquine (HCQ) on PEV release and thrombosis were examined. RESULTS: Human and murine trauma results in a significant release of PEVs into circulation compared with healthy controls. These PEVs result in abundant thrombin generation, increased platelet aggregation, decreased bleeding times, and decreased hemorrhage in uncontrolled bleeding. Conversely, PEVs contributed to enhanced venous thrombus formation and were recruited to the developing thrombus site. Interestingly, HCQ treatment resulted in decreased platelet aggregation, decreased PEV release, and reduced deep vein thrombosis burden in mice. CONCLUSIONS: These data demonstrate that trauma results in significant release of PEVs which are both pro-hemostatic and pro-thrombotic. The effects of PEVs can be mitigated by treatment with HCQ, suggesting the potential use as a form of deep vein thrombosis prophylaxis.

Valproic Acid and Neural Apoptosis, Inflammation, and Degeneration 30 Days after Traumatic Brain Injury, Hemorrhagic Shock, and Polytrauma in a Swine Model.

BACKGROUND: A single-dose (150 mg/kg) of valproic acid (VPA) has been shown to decrease brain lesion size and improve neurologic recovery in preclinical models of traumatic brain injury (TBI). However, the longer-term (30 days) impact of single-dose VPA treatment after TBI has not been well evaluated. STUDY DESIGN: Yorkshire swine were subjected to TBI (cortical impact), hemorrhagic shock, and polytrauma. Animals remained in hypovolemic shock for 2 hours before resuscitation with normal saline (NS; volume = 3× hemorrhaged volume) or NS + VPA (150 mg/kg) (n = 5/cohort). Brain samples were harvested 30 days after injuries. The cerebral cortex adjacent to the site of cortical impact was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, and Western blot analysis. Neural apoptosis, inflammation, degeneration, plasticity, and signaling pathways were evaluated. RESULTS: For apoptosis, VPA treatment significantly decreased (p < 0.05) the number of TUNEL (+) cells and expression of cleaved-caspase 3. For inflammation and degeneration, expression of ionized calcium binding adaptor molecule-1, glial fibrillary acid protein, amyloid-ß, and phosphorylated-Tau protein were significantly attenuated (p < 0.05) in the VPA-treated animals compared with the NS group. For, plasticity, VPA treatment also increased expression of brain-derived neurotrophic factor significantly (p < 0.05) compared with the NS group. For signaling pathways, nuclear factor-κB was decreased significantly (p < 0.05) and cytosolic IκBα expression was increased significantly (p < 0.05) in the VPA-treated animals compared with the NS group. CONCLUSIONS: Administration of a single dose of VPA (150 mg/kg) can decrease neural apoptosis, inflammation, and degenerative changes, and promote neural plasticity at 30 days after TBI. In addition, VPA acts, in part, via regulation of nuclear factor-κB and IκBα pathways.

Histone Deacetylase Inhibitors: A Novel Strategy in Trauma and Sepsis.

Trauma remains a leading cause of morbidity and mortality among all age groups in the United States. Hemorrhagic shock and traumatic brain injury (TBI) are major causes of preventable death in trauma. Initial treatment involves fluid resuscitation to improve the intravascular volume. Although crystalloids may provide volume expansion, they do not have any pro-survival properties. Furthermore, aggressive fluid resuscitation can provoke a severe inflammatory response and worsen clinical outcomes. Due to logistical constraints, however, definitive resuscitation with blood products is often not feasible in the prehospital setting-highlighting the importance of adjunctive therapies. In recent years, histone deacetylase inhibitors (HDACis) have shown promise as pharmacologic agents for use in both trauma and sepsis. In this review, we discuss the role of histone deacetylases (HDACs) and pharmacologic agents that inhibit them (HDACis). We also highlight the therapeutic effects and mechanisms of action of HDACis in hemorrhagic shock, TBI, polytrauma, and sepsis. With further investigation and translation, HDACis have the potential to be a high-impact adjunctive therapy to traditional resuscitation.

Hemostatic nanoparticles increase survival, mitigate neuropathology and alleviate anxiety in a rodent blast trauma model.

Explosions account for 79% of combat related injuries and often lead to polytrauma, a majority of which include blast-induced traumatic brain injuries (bTBI). These injuries lead to internal bleeding in multiple organs and, in the case of bTBI, long term neurological deficits. Currently, there are no treatments for internal bleeding beyond fluid resuscitation and surgery. There is also a dearth of treatments for TBI. We have developed a novel approach using hemostatic nanoparticles that encapsulate an anti-inflammatory, dexamethasone, to stop the bleeding and reduce inflammation after injury. We hypothesize that this will improve not only survival but long term functional outcomes after blast polytrauma. Poly(lactic-co-glycolic acid) hemostatic nanoparticles encapsulating dexamethasone (hDNPs) were fabricated and tested following injury along with appropriate controls. Rats were exposed to a single blast wave using an Advanced Blast Simulator, inducing primary blast lung and bTBI. Survival was elevated in the hDNPs group compared to controls. Elevated anxiety parameters were found in the controls, compared to hDNPs. Histological analysis indicated that apoptosis and blood-brain barrier disruption in the amygdala were significantly increased in the controls compared to the hDNPs and sham groups. Immediate intervention is crucial to mitigate injury mechanisms that contribute to emotional deficits.

Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage.

Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ dysfunction syndrome (MODS). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MODS are also not fully elucidated. As a result, successful therapies for trauma-related MODS are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through toll-like receptor-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. We aimed to determine whether mtDNA released after clinical trauma hemorrhage is sufficient for the development of MODS. Secondly, we aimed to determine the extent of mtDNA release with varying degrees of tissue injury and hemorrhagic shock in a clinically relevant rodent model. Our final aim was to determine whether neutralizing mtDNA with the nucleic acid scavenging polymer, hexadimethrine bromide (HDMBr), at a clinically relevant time point in vivo would reduce the severity of organ injury in this model. CONCLUSIONS: We have shown that the release of mtDNA is sufficient for the development of multiple organ injury. MtDNA concentrations likely peak at different points in the early postinjury phase dependent on the degree of isolated trauma vs combined trauma and hemorrhagic shock. HDMBr scavenging of circulating mtDNA (and nuclear DNA, nDNA) is associated with rescue from severe multiple organ injury in the animal model. This suggests that HDMBr could have utility in rescue from human trauma-induced MODS.

RECENT PRINCIPLES OF ANTIMICROBIAL TREATMENT IN POLYTRAUMA INDUCED SEPSIS AND SEPTIC SHOCK (REVIEW).

20% of trauma deaths occur late after the injury. It is usually the result of sepsis, multi-system organ failure, or other complications. In Polytrauma induced sepsis and septic shock patients, antibacterial management is crucial. The knowledge of recent aspects of treatment is decreasing the costs and the resistance of pathogens, morbidity and mortality. Different models of treatment are suggested by authors, basically they are depended on: the patients age, there health condition, the factors of immunodeficiency, at the location of infection and others. Using the key words, the search engines produced articles. The review was made on the studies about Polytrauma induced sepsis and septic shock patients, about their antimicrobial treatment dosage and duration, about the source control and about the methods of early identification of pathogens (Bacteria and Candida). The advantages and disadvantages of early identification were also studied. Also the role if biomarkers were also reviewed. Based on the review, recommendations are given about the recent principles of antibacterial treatment of Polytrauma induced sepsis and septic shock patients.

Why Methylene Blue Have to Be Always Present in the Stocking of Emergency Antidotes.

Evidence-based review of the existing literature ultimately recommends stocking of Methylene Blue (MB) as an emergency antidote in the United States. The same is reported around the world in Japan, Greece, Italy and Canada. The observation that MB is always present as the main antidote required in emergency and critical care units calls for a revisit on its effects on the NO/cGMP system to reemphasize its multisystem actions. Therefore, the present review aimed to display the role of MB in emergency units, concerning: 1) Polytrauma and circulatory shock; 2) Neuroprotection, 3) Anaphylaxis and, 4) Overdose and poisoning.