The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model.

BACKGROUND: The early use of tranexamic acid (TXA) is strongly advocated in patients who are likely to require massive transfusion to decrease mortality. This study determines the influence of hemorrhage on the pharmacokinetics of TXA in a porcine model. METHODS: The investigation was a prospective experimental study in Yucatan minipigs. First, in vitro plasma-cell partitioning of TXA was evaluated by inoculating whole blood with known aliquots, centrifuging, and measuring the supernatant with high-performance liquid chromatography with mass spectrometry (HPLC-MS). Then, using in vivo modeling, normovolemic and hypovolemic (35% reduction in blood volume) swine (n = 4 per group) received 1 g of intravenous TXA and had blood sampled at 14 time points over 4 hours to determine baseline clearance via HPLC-MS. Additional swine (n = 4) were hemorrhaged 35% of their blood volume, and TXA was administered as a 15 mg/kg infusion over 10 minutes followed by infusion of 1.875 mg/kg per hour to simulate massive hemorrhage scenario. During the first hour of TXA administration, one total blood volume was hemorrhaged and simultaneously replaced with TXA free blood. Serial blood samples and the hemorrhaged blood were analyzed by HPLC-MS to determine the percentage of dose lost via hemorrhage. RESULTS: Clearance of TXA was diminished in the hypovolemic group compared with the normovolemic group (115 ± 4 vs 70 ± 7 mL/min). Percentage of dose lost via hemorrhage averaged 25%. The lowest measured plasma level during the exchange transfusion was 34 µg/mL. CONCLUSION: Mean 25% of the present 2017 Joint Trauma System Clinical Practice Guideline dosing of TXA can be lost to hemorrhage if a blood volume is transfused within an hour of initiating therapy. In the case of TXA, which has limited distribution and is administered during active hemorrhage and massive blood transfusions, replacement strategies should be developed and tested to find simple methods of adjusting the current dosing guidelines to maintain therapeutic plasma concentrations. LEVEL OF EVIDENCE: Therapeutic, level II.

Ultra-Performance Liquid Chromatography-Mass Spectrometry Analysis of Free and Esterified Oxygenated Derivatives from Docosahexaenoic Acid in Rat Brain.

Docosahexaenoic acid (DHA), a prominent long-chain fatty acid of the omega-3 family, is present at high amount in brain tissues, especially in membrane phospholipids. This polyunsaturated fatty acid is the precursor of various oxygenated lipid mediators involved in diverse physiological and pathophysiological processes. Characterization of DHA-oxygenated metabolites is therefore crucial for better understanding the biological roles of DHA. In this study, we identified and measured, by ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry, a number of oxygenated products derived from DHA in exsanguinated and nonexsanguinated brains. These metabolites were found both in free form and esterified in phospholipids. Interestingly, both (R)- and (S)-monohydroxylated fatty acid stereoisomers were observed free and esterified in phospholipids. Monohydroxylated metabolites were the main derivatives; however, measurable amounts of dihydroxylated products such as protectin DX were detected. Moreover, exsanguination allowed discriminating brain oxygenated metabolites from those generated in blood. These results obtained in healthy rats allowed an overview on the brain oxygenated metabolism of DHA, which deserves further research in pathophysiological conditions, especially in neurodegenerative diseases.