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.

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.

Is Opioid Prescribing Driving Trauma Recidivism or Is Trauma Driving Opioid Use?

In the past 30 years, opioid prescription rates have quadrupled and hospital admissions for overdose are rising. Previous studies have focused on alcohol use and trauma recidivism, however rarely evaluating recidivism and opioid use. We hypothesized there is an association between opioid use and trauma recidivism. This is a retrospective review of patients with multiple admissions for traumatic injury. Demographics, opioid toxicology screen (TS) results, and injury characteristics were collected. Statistical analysis was performed with chi-squared and Poisson regression models. One thousand six hundred forty-nine patients (age ≥18 years) had multiple trauma admissions. Seven hundred nine patients had TS data for both admissions. Thirty-one per cent (218) were TS positive on the 1st admission compared with 34 per cent (244) on their 2nd admission. Fifty-five per cent of patients who were TS positive on the 1st admission were positive on their 2nd admission, whereas 25 per cent who were TS negative on the 1st admission were subsequently positive on their 2nd admission (P < 0.0001). Patients who were TS positive on the subsequent admission were less severely injured than TS negative patients (Injury Severity Score > 15, 26.3% vs 22.3%, P = 0.04). The only significant risk factor for being TS positive on the 2nd admission was being TS positive on the 1st admission (relative risk = 2.18, P < 0.001). A previous history of opioid use is the strongest predictor of recurrent use in recidivists.

An obligatory role of NF-κB in mediating bone marrow derived endothelial progenitor cell recruitment and proliferation following endotoxemic multiple organ injury in mice.

BACKGROUND: Recruitment of bone marrow derived endothelial progenitor cells (BMDEPCs) alleviates multiple organ injury (MOI) and improves outcomes. However, mechanisms mediating BMDEPC recruitment following septic MOI remain largely unknown. This study characterized the kinetics of BMDEPC recruitment and proliferation and defined the role of NF-κB in regulating BMDEPC recruitment and proliferation. METHODS AND MAIN FINDINGS: Chimeric mice with an intact or disrupted NF-κB p50 gene and BMDEPC-restricted expression of green fluorescent protein were created and injected with LPS (2 mg/kg, i.p.). BMDEPC recruitment and proliferation in multiple organs were quantified. BMDEPC recruitment and proliferation are highly organ-dependent. Lungs had the highest number of BMDEPC recruitment, whereas heart, liver and kidney had only a small fraction of the number of BMDEPCs in lungs. Number of proliferating BMDEPCs was several-fold higher in lungs than in other 3 organs. Kinetically, BMDEPC recruitment into different organs showed different time course profiles. NF-κB plays obligatory roles in mediating BMDEPC recruitment and proliferation. Universal deletion of NF-κB p50 gene inhibited LPS-induced BMDEPC recruitment and proliferation by 95% and 69% in heart. However, the contribution of NF-κB to these regulations varies significantly between organs. In liver, universal p50 gene deletion reduced LPS-induced BMDEPC recruitment and proliferation only by 49% and 35%. NF-κB activities in different tissue compartments play distinct roles. Selective p50 gene deletion either in stromal/parenchymal cells or in BM/blood cells inhibited BMDEPC recruitment by a similar extent. However, selective p50 gene deletion in BM/blood cells inhibited, but in stromal/parenchymal cells augmented BMDEPC proliferation. CONCLUSIONS: BMDEPC recruitment and proliferation display different kinetics in different organs following endotoxemic MOI. NF-κB plays obligatory and organ-dependent roles in regulating BMDEPC recruitment and proliferation. NF-κB activities in different tissue compartments play distinct roles in regulating BMDEPC proliferation.

[Analysis of exposure to pepper spray as a part of preparing hospital to help victims of mass chemical incidents]. / Analiza narazenia na gaz pieprzowy jako element przygotowania szpitala do pomocy ofiarom masowych skazen chemicznych.

We analyzed an incident of exposure to pepper spray 35 persons, including 29 children. Medical procedures were difficult because of the lack of reliable information about the nature of exposure, lack of hospital action plan for chemical accidents and established principles of cooperation with poison control center, as well as the need of extensive medical documentation for each patient.

Bilateral simultaneous femoral diaphyseal fractures in a patient with long-term ibandronate use.

Bisphosphonates are the most common medication used to treat patients with documented osteoporosis. Recently, reports have associated long-term bisphosphonate use with low-energy femur fractures. While no definitive mechanism has been associated, bisphosphonate use has been strongly implicated. This article presents the case of a 65-year-old woman with a 2-year history of ibandronate use presenting with simultaneous low-energy femoral shaft fractures. The patient reported prodromal bilateral thigh pain and was seen by a spine surgeon. A review of the literature implicates long-term ibandronate use in low-energy femur fractures. With most of the basic science studies demonstrating suppressed bone turnover after 5 years of treatment with alendronate, the significance of the present case also lies in the relatively short duration of time the patient was on ibandronate before suffering the bilateral femoral shaft fractures. Possible pathophysiology for the fractures includes suppressed bone turnover that may allow microcracks to propagate in cortical bone, which can weaken the bone and possibly predispose it to fractures. Patients who have been on bisphosphonates long term should be questioned about thigh pain and have radiographs of their femurs obtained if pain exists. Furthermore, if a patient presents with a single subtrochanteric or diaphyseal low-energy femur fracture after long-term bisphosphonate use, a radiograph of the contralateral femur should be obtained to assess for a cortical stress reaction.

Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy.

BACKGROUND: While alendronate therapy has been shown to decrease the risk of vertebral and femoral neck fractures in postmenopausal osteoporotic patients, recent reports have associated long-term alendronate therapy with unilateral low-energy subtrochanteric and diaphyseal femoral fractures in a small number of patients. To our knowledge, there has been only one report of sequential bilateral femoral fractures in patients on long-term bisphosphonate therapy. METHODS: We retrospectively reviewed the case log of the senior author over the last four years to identify patients who presented with a subtrochanteric or diaphyseal femoral fracture after a low-energy mechanism of injury (a fall from standing height or less) and who had been taking alendronate for more than five years. Radiographs were reviewed, and the fracture patterns were recorded. Serum calcium levels were recorded when available. RESULTS: Seven patients who sustained low-energy bilateral subtrochanteric or diaphyseal femoral fractures while on long-term alendronate therapy were identified. One patient presented with simultaneous bilateral diaphyseal fractures, two patients had sequential subtrochanteric fractures, and four patients had impending contralateral subtrochanteric stress fractures noted at the time of the initial fracture. Of the latter four, one patient had a fracture through the stress site and the other three patients had prophylactic stabilization of the site with internal fixation. No patient had discontinued alendronate therapy prior to the second fracture. All patients were women with an average age of sixty-one years, and they had been on alendronate therapy for an average of 8.6 years. All fractures were treated with reamed intramedullary nailing and went on to union at an average of four months. CONCLUSIONS: In patients on long-term alendronate therapy who present with a subtrochanteric or diaphyseal femoral fracture, we recommend radiographs of the contralateral femur and consideration of discontinuing alendronate in consultation with an endocrinologist. If a contralateral stress fracture is found, prophylactic fixation should be considered.

Atraumatic bilateral femur fracture in long-term bisphosphonate use.

Postmenopausal women with osteoporosis are commonly treated with the bisphosphonate class of medications, one of the most frequently prescribed medications in the United States. In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures. This article presents a case of a 67-year-old woman who presented with an atraumatic right femur fracture. She had a medical history notable for use of the bisphosphonate alendronate for 16 years before being switched to ibandronate for 1 year before presentation. She had sustained a similar fracture on the contralateral side 3 years previously. This case report, in addition to a review of the literature, shows that use of the bisphosphonate class of medications for an extended period of time may result in an increased susceptibility to atraumatic femoral diaphyseal fractures. Some studies have suggested that the reason may be the mechanism of action of bisphosphonates, resulting in decreased bone turnover and remodeling. Studies have not shown if the entire class of medications produce a similar result, but patients who have been treated with any bisphosphonate for an extended period of time should be considered at risk. In patients who have already sustained a femoral diaphyseal fracture, imaging of the contralateral side should be performed to identify cortical thickening as an early sign of fracture risk. Patients should also be questioned about thigh pain.

Bilateral femoral neck fractures in long-term steroid use for systemic lupus erythematosus and chronic lung disease.

Bilateral femoral neck fractures present a rare injury. Only one report to our knowledge was not related to an acute severe traumatic event, and developed years after pelvic irradiation. Chronic steroid use may severely decrease bone strength, thus increasing the risk for such an injury. Patients with chronic lung disease and chronic inflammatory conditions are frequently treated with steroids such as prednisone at doses that may exceed 2.5 mg a day for long durations. Fractures at vulnerable sites such as the femoral neck may then follow without any severe trauma. Awareness of the detrimental effect of chronic steroid consumption on bone morphology, and familiarity with treatment alternatives to improve bone mass is important to prevent such a severe injury. We describe two cases of bilateral femoral neck fractures in women who were treated for years with orally administered prednisone. The rarity of such an injury of bilateral hip fractures and the fact that neither of the patients sustained major trauma, strongly suggests that both cases were related to impaired bone metabolism due to the effect of prolonged steroid consumption. The biological effects of different roots of steroid administration on bone turnover, as well as several strategies that can be implemented by clinicians to treat and prevent steroid induced osteoporosis and fractures, are further clarified in this article.

[Successive ruptures of patellar and Achilles tendons. Anabolic steroids in competitive sports]. / Mehrzeitige Rupturen von Patellar- und Achillessehnen. Anabole Steroide im Leistungssport.

Derivatives of testosterone or of 19-nor-testosterone are used as anabolics for the purpose of improving performance although the effect of anabolics is known still to be under discussion. The use of anabolic steroids continues among competitive athletes despite increased controls and increasingly frequent dramatic incidents connected with them. Whereas metabolic dysfunction during anabolic use is well documented, ruptures of the large tendons are rarely reported. Within 18 months, a 29-year-old professional footballer needed surgery for rupture of the patellar tendon and of both Achilles tendons. Carefully directed questioning elicited confirmation that he had taken different anabolic steroids regularly for 3 years with the intention of improving his strength. After each operation anabolic steroids were taken again at a high dosage during early convalescence and training. Minimally invasive surgery and open suturing techniques led to complete union of the Achilles tendons in good time. Training and anabolic use (metenolon 300 mg per week) started early after suturing of the patellar tendon including bone tunnels culminated in histologically confirmed rerupture after 8 weeks. After a ligament reconstruction with a semitendinosus tendon graft with subsequent infection, the tendon and reserve traction apparatus were lost. Repeated warnings of impaired healing if anabolic use was continued had been given without success. In view of the high number of unrecorded cases in competitive and athletic sports, we can assume that the use of anabolic steroids is also of quantitative relevance in the operative treatment of tendon ruptures.

[Quality management of interdisciplinary treatment of polytrauma. Possibilities and limits of retrospective routine data collection]. / Qualitätssicherung interdisziplinärer Polytraumaversorgung. Möglichkeiten und Grenzen retrospektiver Standarderfassung.

BACKGROUND: The purpose of this study was to evaluate the quality of interdisciplinary multiple trauma management using routinely taken data. METHODS: A retrospective analysis of all multiple traumatized patients [Injury Severity Score (ISS)>15] in a university hospital (n=172; time period 01.01.1997-31.12.1999) was carried out concerning epidemiological and clinical variables and hospital outcome (p<0.05). RESULTS: The overall mortality was 22% [n=38; expected Trauma Injury Severity Score (TRISS) mortality 29%]. Significant parameters for worse outcome in univariate analysis were age>74 years, hypotension, decreasing hemoglobin level and prothrombin time, decreased Glasgow Coma Scale and the number of erythrocyte or plasma concentrates received in the initial period of treatment. The comparison of our results with the data of the German Association for Trauma Surgery registry demonstrated comparable results with respect to management sequence and outcome. CONCLUSIONS: In the quality management of multiple trauma patients retrospective analysis of routinely registered parameters can be a reliable and practical alternative to time-consuming prospective studies when based on prognostic relevant data. Such a procedure allows a preliminary critical comparison with other centers.

Medical management of the traumatic consequences of civil unrest incidents: causation, clinical approaches, needs and advanced planning criteria.

In the context of this review, civil unrest is defined as disharmony, expressive dissatisfaction and/or disagreement between members of a community, which leads to a situation of competitive aggression that may find expression as disruption of organisation, conflicts, damage to property and injuries. Such a breakdown of harmonious relationships, which may result in property damage and human injuries that may be threatening to life, varies in magnitude from participation of a very few individuals up to the involvement of large crowds of people, which may evolve into a full-scale riot. It is the latter situation often involving demonstrators, opposing groups and law enforcement personnel that can result in multiple casualties and present a very significant challenge to the resources of local healthcare institutions. The causation of civil unrest incidents is multifactorial and has generic, specific and potentiating elements. With the current national and international societal, political and discriminatory problems, it is likely that civil unrest incidents on both small and large scales will continue to occur at a high and possibly increasing rate on a worldwide basis, and for these not infrequent incidents, the medical community should be in a state of informed preparation. The circumstances of civil unrest incidents are very variable with respect to causation, overall magnitude, frequency, timing, geographical location, numbers of persons involved, demographics of participants, influence of extremists, confrontation with opposing groups and control measures used by law enforcement agencies. Methods used by police and security forces for the control of civil unrest incidents, if advanced negotiations with organisers and verbal warnings have failed, fall basically into two categories: physical and chemical measures. Physical methods include restraint holds, truncheons, batons, mounted horses, projectiles (such as bean bags, plastic and rubber bullets), water cannons, tasers and (rarely) live ammunition. All of these physical measures are associated with pain and immobilisation, and there is a high potential for soft tissue and bone injuries. Some of the more severe physical methods, including plastic and rubber bullets, may cause lethal injuries. The basis for using chemicals in civil unrest incidents is that they cause distraction, transient harassment and incapacitation, temporary impairment of the conduct of coordinated tasks and cause a desire to vacate the area of unrest. Although screening smokes and malodors have sometimes been employed, the major group of chemicals used are peripheral chemosensory irritants (PCSIs), which reversibly interact with sensory nerve receptors in exposed skin and mucosal surfaces, resulting in the production of local uncomfortable sensations and associated reflexes. Major effects are on the eye, respiratory tract and (to a lesser degree) skin. Thus, the induced transient pain and discomfort in the eye, respiratory tract and skin, together with associated lacrimation, blepharospasm, rhinorrhoea, sialorrhoea, cough and breathing difficulties, produce temporary incapacitation and interference with the conduct of coordinated tasks, and form the basis for harassment of malefactors. Currently used peripheral chemosensory irritants are 1-chloroacetophenone, 2-chlorobenzylidene malononitrile, dibenz(b.f)-1,4-oxazepine, oleoresin capsicum and pelargonic acid vanillylamide. Depending on operational circumstances, irritants may be dispersed as a smoke, powder cloud, aerosol, vapour, or in solution; the mode of generation and dispersion of irritant can influence hazard. Brief acute exposure to chemosensory irritants produces effects that generally resolve within an hour, leaving no long-term sequelae. However, sustained exposure to high concentrations may produce tissue injury, notably to the eye, respiratory tract and skin. With solutions of sensory irritants, other formulation constituents may enhance PCSI toxicity or introduce additional local and/or systemic toxicity. By the very circumstances of civil unrest incidents, injuries are inevitable, particularly when emotions are heightened and police and security forces have to resort to various chemical and/or physical means of control. Trauma may include slight to severe physical and/or chemical injuries, psychological problems and occasional deaths. Hospitals should be prepared for a wide range of casualties, and the fact that those seeking help will constitute a heterogeneous group, including wide age range, male, female, and individuals with pre-existing ill health. A major civil unrest incident necessitates that the local receiving hospital should be prepared and equipped for decontamination and triage processes. It is necessary to reassure patients who have been exposed to sensory irritants that the signs and symptoms are rapidly reversible, and do not result in long-term sequelae. With respect to chemical exposures, detailed evaluation should be given to possible ocular, cutaneous, respiratory and gastrointestinal effects. Also, exposure to chemosensory irritants results in transient increases in blood pressure, bradycardia and increased intraocular pressure. This indicates that those with cardiovascular diseases and glaucoma may be at increased risk for the development of complications. This article details the pharmacological, toxicological and clinical effects of chemicals used in civil disturbance control and discusses the management of contaminated individuals. Additionally, the potential for adverse effects from delivery systems and other physical restraint procedures is summarised. Due to the emergency and specialised circumstances and conditions of a civil unrest incident, there is a clear need for advanced planning by healthcare institutions in the event that such an incident occurs in their catchment area. This should include ensuring a good information base, preparations for medical and support staff readiness, and availability of required equipment and medications. Ideally, planning, administration and coordination should be undertaken at both local (regional) and central (governmental) centres. Regional centres should have responsibilities for education, training, ensuring facilities and staffing are appropriate, and that adequate equipment and medicines are available. There should be cooperative interactions and communications with local police and other emergency services. Centrally directed functions should include ensuring adequacy of the information base, coordinating activities and agreeing approaches between the regional centres, and periodic audits of regional centres with respect to the staffing, facility, equipment and training needs. Also, there is a need for most countries to introduce detailed guidelines and formal (regulatory) schemes for the assessment of the safety-in-use of chemicals and the delivery systems that are to be used against heterogeneous human populations for the control of civil unrest incidents. Such regulatory approval schemes should also cover advisory functions for safe use and any required restrictions.

Major trauma in elderly adults receiving lipid-lowering medications.

BACKGROUND: Some clinical trials, laboratory experiments, and in vitro studies suggest that lipid-lowering medications predispose a person to traumatic injury. METHODS: We used population-based administrative database analysis to study adults age 65 years or more over a 5-year interval (n = 1,348,259). RESULTS: About 12% of the cohort received a prescription for a lipid-lowering medication and about 88% did not. The two groups had similar distributions of age, gender, and income. Overall, 2,557 (0.2%) were hospitalized for major trauma. Those who received a lipid-lowering medication were 39% less likely to sustain a major trauma than those who did not receive such medication (95% confidence interval, 29 to 47). Similar results were observed after adjustment for age, gender, and income; cardiac and neurologic medications; and lethality. No other cardiac or neurologic medication was associated with an apparent safety advantage. CONCLUSION: Lipid-lowering medications do not lead to a clinically important increase in the absolute risk of major trauma for elderly patients in the community.

Multiple organ failure (MOF) after severe trauma--a sheep model.

OBJECTIVE: To perform a reproducible long-term (10 days) large animal model of multiple systems organ failure without necessity of a continuous stimulus. DESIGN: Adult female merino sheep submitted to a 5-day stimulation period followed by a 5-day observation period. Day 1: Hemorrhagic shock was combined with a traumatic surgical insult (reamed intramedullary femoral nailing), followed by serial administrations every 12 h for 5 days of a combination of endotoxin and zymosan activated plasma. Organ function was followed for 5 further days. RESULTS: Cardiac index increased significantly during the study (day 1: 491 +/- 8 mm Hg; day 10: 427 +/- 20, p < 0.05). Liver function was impaired and bilirubin levels increased significantly (day 1: 2.9 +/- 0.3 micromol/l; day 10: 7.2 +/- 0.9; p < 0.05). Creatinine clearance decreased initially (day 1: 54 +/- 7 ml/min), increased to a peak on day 2 (104 +/- 27), and then deteriorated again (day 10: 53 +/- 18). CONCLUSION: This new large animal model of trauma-induced MOF is reproducible and may be suitable for the study of new therapeutic approaches to therapy.

[Treatment of isolated and combined burns of the stomach]. / Lechenie izolirovannykh i sochetannykh ozhogovykh porazhenii zheludka.

Results of the surgical treatment of 31 patients with isolated and associated burn injuries of the stomach are presented. Resection of the stomach was performed on 24 patients (15 patients--by Billroth-1 and 9 patients--by Billroth-2 method). A necessary procedure is the intraoperative forced bougieurage under narcosis of the scarry esophagus. Two patients died: one of them after gastric resection, the second--after making collateral gastroenteroanastomosis from incompetent sutures of anastomosis, peritonitis. Successful treatment is dependent on the timely diagnosis and rational curative tactics.