Intramuscular Tranexamic Acid in Tactical and Combat Settings.

BACKGROUND: Uncontrolled hemorrhage remains a leading cause of preventable death in tactical and combat settings. Alternate routes of delivery of tranexamic acid (TXA), an adjunct in the management of hemorrhagic shock, are being studied. A working group for the Committee for Tactical Emergency Casualty Care reviewed the available evidence on the potential role for intramuscular (IM) administration of TXA in nonhospital settings as soon as possible from the point of injury. METHODS: EMBASE and MEDLINE/PubMed databases were sequentially searched by medical librarians for evidence of TXA use in the following contexts and/or using the following keywords: prehospital, trauma, hemorrhagic shock, optimal timing, optimal dose, safe volume, incidence of venous thromboembolism (VTE), IM bioavailability. RESULTS: A total of 183 studies were reviewed. The strength of the available data was variable, generally weak in quality, and included laboratory research, case reports, retrospective observational reviews, and few prospective studies. Current volume and concentrations of available formulations of TXA make it, in theory, amenable to IM injection. Current bestpractice guidelines for large-volume injection (i.e., 5mL) support IM administration in four locations in the adult human body. One case series suggests complete bioavailability of IM TXA in healthy patients. Data are lacking on the efficacy and safety of IM TXA in hemorrhagic shock. CONCLUSION: There is currently insufficient evidence to support a strong recommendation for or against IM administration of TXA in the combat setting; however, there is an abundance of literature demonstrating efficacy and safety of TXA use in a broad range of patient populations. Balancing the available data and risk- benefit ratio, IM TXA should be considered a viable treatment option for tactical and combat applications. Additional studies should focus on the optimal dose and bioavailability of IM dosing of patients in hemorrhagic shock, with assessment of potential downstream sequelae.

Munc18b is a major mediator of insulin exocytosis in rat pancreatic ß-cells.

Sec1/Munc18 proteins facilitate the formation of trans-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes that mediate fusion of secretory granule (SG) with plasma membrane (PM). The capacity of pancreatic ß-cells to exocytose insulin becomes compromised in diabetes. ß-Cells express three Munc18 isoforms of which the role of Munc18b is unknown. We found that Munc18b depletion in rat islets disabled SNARE complex formation formed by syntaxin (Syn)-2 and Syn-3. Two-photon imaging analysis revealed in Munc18b-depleted ß-cells a 40% reduction in primary exocytosis (SG-PM fusion) and abrogation of almost all sequential SG-SG fusion, together accounting for a 50% reduction in glucose-stimulated insulin secretion (GSIS). In contrast, gain-of-function expression of Munc18b wild-type and, more so, dominant-positive K314L/R315L mutant promoted the assembly of cognate SNARE complexes, which caused potentiation of biphasic GSIS. We found that this was attributed to a more than threefold enhancement of both primary exocytosis and sequential SG-SG fusion, including long-chain fusion (6-8 SGs) not normally (2-3 SG fusion) observed. Thus, Munc18b-mediated exocytosis may be deployed to increase secretory efficiency of SGs in deeper cytosolic layers of ß-cells as well as additional primary exocytosis, which may open new avenues of therapy development for diabetes.