Prehospital Tranexamic Acid Administration During Aeromedical Transport After Injury.

BACKGROUND: Tranexamic acid (TXA) has been shown to reduce mortality in the treatment of traumatic hemorrhage. This effect seems most profound when given early after injury. We hypothesized that extending a protocol for TXA administration into the prehospital aeromedical setting would improve outcomes while maintaining a similar safety profile to TXA dosed in the emergency department (ED). MATERIALS AND METHODS: We identified all trauma patients who received TXA during prehospital aeromedical transport or in the ED at our urban level I trauma center over an 18-mo period. These patients had been selected prospectively for TXA administration using a protocol that selected adult trauma patients with high-risk mechanism and concern for severe hemorrhage to receive TXA. Patient demographics, vital signs, lab values including thromboelastography, blood administration, mortality, and complications were reviewed retrospectively and analyzed. RESULTS: One hundred sixteen patients were identified (62 prehospital versus 54 ED). Prehospital TXA patients were more likely to have sustained blunt injury (76% prehospital versus 46% ED, P = 0.002). There were no differences between groups in injury severity score or initial vital signs. There were no differences in complication rates or mortality. Patients receiving TXA had higher rates of venous thromboembolic events (8.1% in prehospital and 18.5% in ED) than the overall trauma population (2.1%, P < 0.001). CONCLUSIONS: Prehospital administration of TXA during aeromedical transport did not improve survival compared with ED administration. Treatment with TXA was associated with increased risk of venous thromboembolic events. Prehospital TXA protocols should be refined to identify patients with severe hemorrhagic shock or traumatic brain injury.

Do Autopsies Still Matter? The Influence of Autopsy Data on Final Injury Severity Score Calculations.

BACKGROUND: Despite a proven record of identifying injuries missed during clinical evaluation, the effect of autopsy on injury severity score (ISS) calculation is unknown. We hypothesized that autopsy data would alter final ISS and improve the accuracy of outcome data analyses. MATERIALS AND METHODS: All trauma deaths from January 2010 through June 2014 were reviewed. Trauma registrars calculated Abbreviated Injury Scale and ISS from clinical documentation alone. The most detailed available autopsy report then was reviewed, and AIS/ISS recalculated. Predictors of ISS change were identified using multivariate logistic regression. RESULTS: Seven hundred thirty-nine deaths occurred, of which 682 (92.3%) underwent autopsy (31% view-only, 3% with preliminary report, and 66% with full report). Patients undergoing full autopsy had a lower median age (39 versus 74 years, P < 0.01), a higher rate of penetrating injury (41.7% versus 0%, P < 0.01), and a higher emergency department mortality rate (30.8% versus 0%, P < 0.01) than those receiving view-only autopsy. Incorporating autopsy findings increased mean ISS (21.3 to 29.6, P < 0.001) and the percentage of patients with ISS ≥ 25 (49.9% to 69.2%, P < 0.001). Multivariate analysis identified length of stay, death in the emergency department, full rather than view-only autopsy, and presenting heart rate as variables associated with ISS increase. CONCLUSIONS: Autopsy data significantly increased ISS values for trauma deaths. This effect was greatest in patients who died early in their course. Targeting this group, rather than all trauma patients, for full autopsy may improve risk-adjustment accuracy while minimizing costs.

Impact of tranexamic acid on coagulation and inflammation in murine models of traumatic brain injury and hemorrhage.

BACKGROUND: Posttraumatic coagulopathy and inflammation can exacerbate secondary cerebral damage after traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown clinically to reduce mortality in hemorrhaging and head-injured trauma patients and has the potential to mitigate secondary brain injury with its reported antifibrinolytic and antiinflammatory properties. We hypothesized that TXA would improve posttraumatic coagulation and inflammation in a murine model of TBI alone and in a combined injury model of TBI and hemorrhage (TBI/H). METHODS: An established murine weight drop model was used to induce a moderate TBI. Mice were administered intraperitoneal injections of 10 mg/kg TXA or equivalent volume of saline 10 min after injury. An additional group of mice was subjected to TBI followed by hemorrhagic shock using a pressure-controlled model. TBI/H mice were given intraperitoneal injections of TXA or saline during resuscitation. Blood was collected at intervals after injury to assess coagulation by rotational thromboelastometry (ROTEM) and inflammation by Multiplex cytokine analysis. Soluble P-selectin, a biomarker of platelet activation, and serum neuron-specific enolase, a biomarker of cerebral injury, were measured at intervals. Brain homogenates were analyzed for inflammatory changes by Multiplex enzyme-linked immunosorbent assay, and splenic tissue was collected for splenic cell population assessment by flow cytometry. RESULTS: There were no coagulation, serum or cerebral cytokine, P-selectin, or neuron-specific enolase differences between mice treated with TXA or saline after TBI. After the addition of hemorrhagic shock and resuscitation to TBI, TXA administration still did not affect coagulation parameters, systemic or cerebral inflammation, or platelet activation, as compared with saline alone. At 24 hours after TBI, mice given TXA demonstrated lower splenic total cell counts central memory CD8, effector CD8, B cell, and increased naive CD4 cell populations. By contrast, TXA did not affect splenic leukocyte populations after combined TBI/H. CONCLUSIONS: Despite clinical data suggesting a mortality benefit, TXA did not modulate coagulation, inflammation, or biomarker generation in either the TBI or TBI/H murine models. Administration of TXA after TBI altered splenic leukocyte populations, which may contribute to a change in posttraumatic immune status. Future studies should be done to investigate the role of TXA in the development of posttraumatic immunosuppression and risk of nosocomial infections.

Doxycycline-Coated Silicone Breast Implants Reduce Acute Surgical-Site Infection and Inflammation.

BACKGROUND: Surgical-site infection after implant-based breast reconstruction remains a leading cause of morbidity. Doxycycline is an antibiotic used to treat soft-tissue infections. The authors hypothesize that doxycycline-coated breast implants will significantly reduce biofilm formation, surgical-site infection, and inflammation after bacterial infection. METHODS: Pieces of silicone breast implants were coated in doxycycline. In vitro studies to characterize the coating include Fourier transmission infrared spectroscopy, elution data, and toxicity assays (n = 4). To evaluate antimicrobial properties, coated implants were studied after methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa inoculation in vitro and in a mouse model at 3 and 7 days (n = 8). Studies included bacterial quantification, cytokine profiles, and histology. RESULTS: Coated silicone breast implants demonstrated a color change, increased mass, and Fourier transmission infrared spectroscopy consistent with a doxycycline coating. Coated implants were nontoxic to fibroblasts and inhibited biofilm formation and bacterial adherence after MRSA and P. aeruginosa incubation in vitro, and measurable doxycycline concentrations at 24 hours were seen. In a mouse model, a significant reduction of MRSA and P. aeruginosa bacterial colonization after 3 and 7 days in the doxycycline-coated implant mice was demonstrated when compared to the control mice, control mice treated with intraperitoneal doxycycline, and control mice treated with a gentamicin/cefazolin/bacitracin wash. Decreased inflammatory cytokines and inflammatory cell infiltration were demonstrated in the doxycycline-coated mice. CONCLUSIONS: A method to coat silicone implants with doxycycline was developed. The authors' doxycycline-coated silicone implants significantly reduced biofilm formation, surgical-site infections, and inflammation. Further studies are needed to evaluate the long-term implications.

Acid Sphingomyelinase Inhibition Mitigates Histopathological and Behavioral Changes in a Murine Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) can lead to the development of chronic traumatic encephalopathy as a result of neuronal phosphorylated tau (p-tau) protein aggregation and neuroinflammation. Acid sphingomyelinase (Asm) may also contribute to post-TBI neurodegenerative disorders. We hypothesized that Asm inhibition would ameliorate p-tau aggregation, neuroinflammation, and behavioral changes after TBI in a murine model. TBI was generated using a weight-drop method. Asm inhibition in wild-type mice was achieved with a single injection of amitriptyline 1 h after TBI. Genetic Asm ablation was achieved using Asm-deficient mice (Asm-/-). Thirty days after TBI, mice underwent behavioral testing with the forced swim test for symptoms of depression or were euthanized for neurohistological analysis. Neuroinflammation was quantified using the microglial markers, ionized calcium-binding adaptor molecule 1 and transmembrane protein 119. Compared to sham mice, TBI mice demonstrated increased hippocampal p-tau. Mice that received amitriptyline after TBI demonstrated decreased p-tau compared to mice that received a saline control. Further, post-TBI Asm-/- mice demonstrated lower levels of p-tau compared to wild-type mice. Though a decrease in neuroinflammation was observed at 1 month post-TBI, no change was demonstrated with mice treated with amitriptyline. Similarly, TBI mice were more likely to show depression compared to mice that received amitriptyline after TBI. Utilizing a weight-drop method to induce moderate TBI, we have shown that genetic deficiency or pharmacological inhibition of Asm prevented hippocampal p-tau aggregation 1 month after injury as well as decreased symptoms of depression. These findings highlight an opportunity to potentially reduce the long-term consequences of TBI.

Sphingolipids and Innate Immunity: A New Approach to Infection in the Post-Antibiotic Era?

Antibiotic resistance has been demonstrated during the entire duration of antibiotic use even before medical utilization. Increasing resistance within virtually all microbes continues to be a problem. Infection with antibiotic resistant microbes has demonstrated significantly increased morbidity, death, and health-care-associated costs. Given increasing antibiotic resistance, multiple novel agents and approaches are being investigated, including antimicrobial lipids. Sphingosine and ceramide have been demonstrated to play a pivotal role in the innate immunity of the epidermis, oral mucosa, and respiratory epithelium; their role is being investigated currently in uroepithelium. Ceramide has been shown to be pivotal in the regulation of mammalian defense against Pseudomonas aeruginosa and Staphylococcus aureus pathogens commonly encountered in pneumonia. On the other hand, sphingosine appears to be equally pivotal and directly involved in pathogenic defense and has been demonstrated to "rescue" mammals from P. aeruginosa infections. Within this review, we will discuss the role of sphingolipids within innate immunity, pathogen invasion, and bacterial infection. We will discuss the antimicrobial activity of sphingosine and possibility for commercial use as an antimicrobial in the post-antibiotic era.

Sphingosine's role in epithelial host defense: A natural antimicrobial and novel therapeutic.

Sphingosine is a natural sphingolipid found in membranes of all eukaryotic cells. In addition to its functions in cell signaling, sphingosine has broad-spectrum antimicrobial properties. Sphingosine's role as an antimicrobial is important in tissues such as the skin and respiratory epithelium. Reduction in the normal sphingosine level is associated with problems related to infection susceptibility. Therefore, exogenous sphingosine may be an effective antimicrobial therapeutic. Inhaled nebulized sphingosine has been shown to be effective at both preventing and treating pneumonia in multiple mouse models. We now show that inhaled sphingosine has low toxicity to the respiratory system, strengthening its case as an excellent candidate for a novel inhaled antimicrobial drug.