Page 40 - JSOM Fall 2020

dose resulted in serum concentrations that may not be benefi- after the time of injury. One study stated that “For the high-
cial past 90 minutes. It is important to note, however, that an est injury acuity patients, TXA was associated with increased,
optimal serum concentration of TXA in trauma has yet to be rather than reduced, mortality, no matter what time it was ad-
determined. 77–79 It is also important to recognize that a 2g dose ministered.” In this study, however, TXA was administered
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has not been specifically studied in patients already in hemor- at a mean time of 97 minutes after arrival at the hospital. The
rhagic shock but has been studied in severely injured patients. range of times was 0 to 886 minutes after arrival. These times
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A recently completed randomized study of prehospital TXA ad- are problematic in that they do not include the elapsed time
ministration in the US compared three dosing strategies, and from injury occurrence until 911 call, the delay to dispatch
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found that the higher dose regimen (2g bolus followed by 1g after the call is received, transit time to the scene of the injury,
infusion) was associated with lower 30 day mortality versus the time on scene, or transport time from the scene to the trauma
lower dose regimens or placebo. Studied dosing outside of the center. This study also suffered from selection bias, resulting in
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trauma literature varies considerably. Most important, however, more severely injured patients in the TXA group, which cannot
is the observation that symptomatic VTE and other adverse ef- be adequately controlled for even with multivariate regression
fects are not increased with dosing up to 30 mg/kg. 2,83–87 TBI techniques. In another published study that concluded there
researchers also found no difference in VTE rate between the was no difference between prehospital and ED administration
1g and 2g prehospital dose. Although a recent review noted of TXA, the prehospital group was noted to receive TXA 51
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the safety and effectiveness of the current dosing protocol, the minutes after EMS dispatch while the ED group received TXA
recommendation to continue with the current TXA dosing reg- 29 minutes after EMS dispatch. In a retrospective review of
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imen did not take into account TBI, the logistical burden of the TXA use in France, TXA administration did not demonstrate
dosing, and the safety profile of a potential change in protocol. 88 in-hospital mortality improvement. These studies highlight
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the challenges in translating data from mature civilian trauma
Does a higher initial dose of TXA cause seizures? There is a systems to TCCC.
historical concern that TXA is associated with an increased
seizure risk, but clinically significant seizures have historically Other studies have reinforced the findings of the CRASH-2
been associated with the much higher doses (>50mg/kg) used timing subgroup analysis that the timing of TXA administra-
in cardiac surgery, rather than the smaller dose of TXA used tion is critical when the possibility of life-threatening bleeding
in trauma patients. 77,89–97 A recent large randomized controlled is considered likely. A large meta-analysis of trauma and
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trial of TXA in TBI patients noted an increased rate of seizures post-partum hemorrhage patients treated with TXA found
at the 2g dose, but these seizures were not found to be associ- that “Immediate treatment improved survival by more than
ated with an increase in adverse outcomes. In CRASH-3, the 70% (OR 1.72, 95% CI 1.42–2.10; p < .0001). Thereafter, the
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observed seizure rate was similar in TXA (3.2%) and placebo survival benefit decreased by 10% for every 15 min of treat-
groups (3.0%). 98 ment delay until 3 h, after which there was no benefit. There
was no increase in vascular occlusive events with tranexamic
Ensuring appropriate criteria for administration of TXA in the acid.” Post-hoc analysis of CRASH-2 data has shown im-
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prehospital setting for TBI was challenging. The change group provement in functional outcomes as well. A meta-analysis
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considered the safety profile of TXA and feedback from pre- of over 28,000 patients published in 2020 found that “about
hospital and emergency medicine providers at the September one-quarter of deaths from bleeding occurred in patients who
2019 CoTCCC meeting in finalizing the recommended guide- initially appeared to have a low risk of death.” The authors
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lines. The initial proposed wording: “If the casualty manifests emphasized early administration of TXA and specifically
signs of significant TBI (blast injury or blunt trauma with loss recommended that TXA “use should not be restricted to the
of consciousness or altered mental status),” was too liberal most severely injured or bleeding patients.” The recently
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given patients in the Emergency Department would not receive reported pre-hospital STAAMP Trial also found that admin-
a head CT based on the criteria above. Utilizing the Glasgow istration of TXA within 1 hour was associated with reduced
Coma Scale (GCS) was proposed as well, but this is cumber- 30-day mortality compared to alternative administration or
some in the prehospital setting. The updated TCCC Guidelines placebo. 82
recommend TXA “If the casualty has signs or symptoms of
significant TBI or has altered mental status associated with In three studies evaluating endotheliopathy in trauma injury, the
blast injury or blunt trauma.” In clarifying specific criteria to effect of TXA was found to be time-dependent and the authors
apply quickly and efficiently in the prehospital setting, trauma supported early administration. 108–110 A large meta-analysis
literature supports the use of only the motor component of the evaluating TXA use in TBI also supported early administra-
GCS. An inability to follow commands, which represents a tion. TXA has also been shown to have anti- inflammatory
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GCS motor score of 5 or less, is an efficient way to determine effects in humans 111–114 and in rodent models. 115–119 These pa-
the threshold for TXA administration in the prehospital set- pers suggest that the additional mechanisms of TXA may also
ting. CRASH-3 identified the greatest benefit of TXA in pa- be time-sensitive. Updated civilian trauma guidelines continue
tients with mild to moderate head injury. In CRASH-3, the to emphasize administration as early as possible following
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GCS was assessed, but the individual components were not trauma. 120
reported. The Emergency Medicine literature has also provided
potential algorithms, but most included the use of CT scans, Is a Second Prehospital Dose of TXA
which are rarely available in the prehospital deployed setting. 101 Really Needed to Improve Outcomes When
Used for Bleeding Trauma Patients?
How Do We Reinforce the Need for Recent literature has questioned the need to initiate an 8 hr
Timely Administration of TXA when Indicated? infusion of a second gram of TXA as part of the prehospital
Some studies have questioned the benefits of TXA in trauma care rendered. Based on the pharmacokinetics of TXA, there
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but based their recommendation on TXA administered well is time after the first dose of TXA to have the casualty arrive at

38 | JSOM Volume 20, Edition 3 / Fall 2020