Tranexamic Acid in Civilian Trauma Care in the California Prehospital Antifibrinolytic Therapy Study

Michael M. Neeki, DO, MS; Fanglong Dong, PhD; Jake Toy, BA; Reza Vaezazizi, MD; Joe Powell, EMT-P; David Wong, MD; Michael Mousselli, BS; Massoud Rabiei, BS; Alex Jabourian, DO; Nichole Niknafs, DO; Michelle Burgett-Moreno, BA; Richard Vara, RN, BSN; Shanna Kissel, RN, MSN; Xian Luo-Owen, MD, PhD; Karen R. O'Bosky, MD; Daniel Ludi, MD; Karl Sporer, MD; Troy Pennington, DO; Tommy Lee, MD; Rodney Borger, MD; Eugene Kwong, MD

Disclosures

Western J Emerg Med. 2018;19(6):977-986. 

In This Article

Discussion

This prospective, observational cohort study with a retrospective comparison investigated the use of prehospital TXA in cases of traumatic hemorrhagic shock and suggested that prehospital TXA use was associated with improved survival outcomes. Reduced mortality was observed at 28 days. To our knowledge, this is the first large-scale, civilian study to systematically examine prehospital TXA administration in trauma patients in North America.

The mortality reduction noted in this study may be attributed to the antifibrinolytic properties of TXA. Evidence suggests that up to 15% of trauma patients may be in a state of hyperfibrinolysis at the scene of injury as noted on rotational thromboelastometry (ROTEM) and more than half of trauma patients may be in a state of moderate to severe fibrinolysis upon arrival to the hospital.[5,7–9,11,23] These coagulopathies often begin within minutes of injury and worsen during transportation from the scene to the hospital.[7,9,11] This process can threaten clot integrity and result in increased blood loss, morbidity, and mortality.[8,9] The antifibrinolytic properties of TXA may act to slow or stop progression of coagulopathies that contribute to excessive blood loss and disruption of hemodynamic stability.

The current study showed a reduction in the total blood products transfused in those administered TXA. However, TXA appears to exert an effect beyond 24 hours, after the risk of bleeding has decreased.[3] This may be a result of the anti-inflammatory effects of TXA that are mediated through a reduction in the magnitude of the plasmin level, thus reducing the pro-inflammatory effect of plasmin.[24,25] This may be responsible for the observed trend toward decreased mortality at 48 hours and longer. Though the exact mechanism is not clear, current evidence demonstrates that the therapeutic mechanism of TXA is likely multifactorial in nature.

In particular, severely injured trauma patients appear to benefit most from TXA. This may be attributed to an increased incidence of acute coagulopathies among patients who have sustained severe traumatic injury as detected on ROTEM.[7,9,26] Thesuinger et al. showed significant deterioration of relevant ROTEM clot parameters between the scene and hospital when TXA was not administered.[7] However, Kunze-Szikszay et al. conducted a follow up study by assessing for acute coagulopathies noted on ROTEM in severely injured trauma patients before and after prehospital TXA administration.[12] Despite no ROTEM changes following prehospital TXA, Kunze-Szikszay et al. concluded that TXA might have reduced unnecessary fibrinogen consumption due to fibrinolysis after comparing their results to those of Theusinger et al. However, the study by Kunze-Szikszay et al. was limited by a small sample size.

Additionally, Moore et al. demonstrated that TXA use in severely injured patients might result in adverse outcomes in select patients in a state of fibrinolysis shutdown or hyperfibrinolysis.[8] Nonetheless, multiple other investigations of TXA use in the civilian prehospital and hospital settings found that TXA was most beneficial among severely injured trauma patients.[19,20,27] Though TXA use in severely injured trauma patients may be beneficial, it appears that both the exact candidate-selection criteria and mechanism of action conferring benefit remain unclear. In addition, mortality in this study may be biased due to differences in mechanism and complexity of injuries sustained by patients.

To date, CRASH-2 represents the only randomized controlled trial assessing TXA in civilian adult trauma.[13] The CRASH-2 findings suggested that TXA administered in the hospital within three hours of injury led to a decrease in all-cause mortality by 1.5% at 28 days. The current study demonstrated a decrease in mortality of 4.7% at 28 days. The corresponding number needed to treat was 22. One major difference between the two studies was the location that TXA was given and the timing of administration. By giving TXA in the prehospital setting, this significantly reduced the time to first dose from 2.8 hours in CRASH-2 to 33 minutes. Further, lack of standardized inclusion protocols between hospitals, many of which were part of underdeveloped trauma systems, along with unclear reporting of adverse events and injury severity, may have impacted the CRASH-2 findings.[19,20]

In regard to assessing the known side-effect profile associated with TXA use, the majority of studies note a limited incidence of adverse events. Though controversial, the CRASH-2 trial reported no increase in thromboembolic events in hospital patients given TXA.[13] Among other observational studies assessing prehospital TXA in the civilian setting, no increases in multiple organ failure, sepsis, or thromboembolic events were noted.[19,20] Notably, a slight increase in thromboembolic events following TXA was noted in a retrospective study in the combat setting; however, authors postulated that a higher injury burden in this setting may have resulted in this finding.[11] The current study showed no significant increase in adverse events following TXA administration.

Notably, two aforementioned neurologic events occurred in patients receiving TXA; however, direct causation between TXA use and each neurologic event was deemed remote, though it could not be definitely excluded. In the first case, a DNR order by the family prevented definitive imaging to assess for traumatic vascular injury vs. a thromboembolic complication secondary to TXA leading to an ischemic stroke. The latter was considered more likely with respect to timing at nearly 40 hours after TXA. Similar to the first case, the second case had a severe mechanism of injury as well as multiple, long bone fractures that likely led to an ischemic stroke that occurred 48 hours after hospital admission. With respect to the mechanism and timing of this neurologic event, direct association with TXA administration appeared to be a less likely etiology, although it cannot be completely excluded. Additionally, no increase in hospital or ICU LOS was noted in the current study, further supporting a relatively non-complicated course among patients administered TXA.

The exact dosing of TXA for traumatic injury remains unclear.[23] A fixed 1 gram dose administered in the field followed by a possible maintenance dose was deemed most practical in the emergency setting.13 In the current study, 64.9% of patients were administered only the first dose of TXA. This may have occurred when a patient no longer satisfied the inclusion criteria for a second TXA dose upon arrival to a participating trauma center. No difference in mortality was observed between those receiving one dose vs. two doses of TXA. If sufficient antifibrinolytic and anti-inflammatory effects occur with only a single dose of TXA, this challenges the apparent need for a maintenance dose. With respect to drug half-life, the duration is unclear in present literature ranging from two to eight hours depending on the dosage.[28–30]

Lastly, our study did not employ coagulation testing before prehospital TXA administration to determine if patients were indeed in a state of hyperfibrinolysis. This significantly limited our ability to administer TXA in a selective fashion. Given the study design and current limitations of point-of-care thromboelastography (TEG) or ROTEM testing, it would have been infeasible to employ such testing in the prehospital setting. Further, previous studies noted the incidence of moderate to severe fibrinolysis at the scene and upon hospital arrival to be over 50%, with fibrinolysis steadily worsening from the scene to the hospital when measured on ROTEM.[7–9] Theusinger et al. concluded that monitoring coagulation via ROTEM at the scene of a trauma would not provide any clinically significant information in the majority of trauma patients.[7] However, upon arrival to the receiving center, growing (but weak) evidence exists suggesting that point-of-care TEG or ROTEM may guide in any additional TXA dosing and blood product administration in critically ill patients.[12,31] At present, administering TXA empirically to those with signs of hemorrhagic shock may be an effective practice until more prehospital point-of-care diagnostic techniques are available.

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