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contributing to lower than expected compliance with guide- 10% of the patients who received TXA were treated within 3
lines. 45,46 The logistical burden comes in several dimensions: the hours of injury. 71
weight and volume of the additional reconstitution fluid bags,
the time it takes to mix the drips and the need to initiate and A retrospective review of 651 patients at a civilian trauma
continue a prolonged infusion while avoiding IV tube interfer- center published in 2019 concluded that TXA use was an “in-
ence and displacement during patient movement. dependent factor associated with lower 30 day mortality in ce-
rebral contusions or traumatic subarachnoid hemorrhage.”
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The logistical challenges of the current dosing protocol in Another retrospective review, this one of military trauma pa-
TCCC motivated the group to explore updated dosing strat- tients, also concluded that TXA was independently associated
egies in trauma. The dosing protocol most widely used, in- with decreased mortality and improved outcomes in head
cluding in the CRASH-2 and CRASH-3 Trials, dates back 25 trauma. In this review, 174 of 265 massive transfusion cases
years. Referred to as the “Horrow Protocol,” this dosing strat- received TXA. The TXA patients had “significantly higher ISS,
egy was compared to others for use in cardiac surgery, with lower presenting GCS, higher incidence of severe head injury
patients on ECMO, and with the first dose being administered and higher transfusion requirements . . . and lower mortality
prior to the initial surgical incision. More recent literature (0% vs 10.1%).” 73
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supports single dose regimens as well, even in cardiac surgery,
with one study noting that a single 1g dose of TXA provided A large meta-analysis published in 2018 explored TXA for
adequate prevention of hyperfibrinolysis compared to 3g + TBI and concluded that TXA “lower(ed) the mortality rate
weighted dose or a single 5g dose. Several articles from the and improv(ed) favorable neurologic outcomes. Another ret-
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orthopedic surgery literature have validated the use of single rospective review found a lower mortality rate for the neu-
dosing regimens. 2,49–52 A meta-analysis including 57 studies, rotrauma patients that received TXA.” 64
published in 2020, that included several surgical disciplines,
also found single dose regimens to be effective. The TCCC In 2019, the results of the largest randomized control trial
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change team acknowledges that caution should be exercised in of TXA in isolated TBI was completed. The CRASH-3 Trial
translating findings from these patient populations to trauma was conducted between 2012 and 2019 in 175 hospitals in
patients. 29 countries and used the Horrow Protocol for TXA dosing.
12,737 patients were included in the study and 6,406 received
TXA. The criteria for TXA administration included (1) pre-
Discussion
sentation within 3 hours of injury, (2) Glasgow Coma Scale
TXA administration has been shown in multiple studies to of 12 or less with any intracranial bleeding on CT, and (3) no
be safe and effective when used for bleeding trauma patients. extracranial bleeding. Overall mortality from head injury was
TXA was incorporated into the TCCC Guidelines in 2011. It 18.5% in the TXA group and 19.8% in the placebo group.
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has since been used in prehospital EMS systems in the United After excluding severe head injury (GCS 3 or non-reactive pu-
States, 55,56 Scandinavia, Canada, Switzerland, France, pils) the mortality from head injury was 12.5% in the TXA
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England, Germany and Israel among others. Literature group and 14% in the placebo group. In a comment pub-
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continues to support the early use of TXA in trauma consis- lished in the same journal, the author noted that “the use of
tent with the findings from CRASH-2 and MATTERs. 59,60,64 28-day head injury-related mortality as the primary endpoint
TXA has been documented repeatedly in the previously refer- probably biased the treatment effect towards the null because
enced publications to reduce blood loss in elective surgery, and tranexamic acid is most likely to benefit patients with TBI with
the sooner blood loss is slowed or stopped in bleeding trauma intracranial bleeding at risk of early mortality.” 75
patients, the more favorable the expected outcome. 65
A recent US randomized controlled trial found a survival bene-
TXA for Casualties with TBI. fit when 2g of TXA was administered in the prehospital phase
As far back as 2012, data suggested “that TXA administration of care to casualties with moderate to severe TBI. In the subset
might improve outcomes in TBI patients and provide grounds of patients who were later noted to have intracranial hemor-
for evaluating this hypothesis in future research.” The inclu- rhage (ICH) on initial CT scan, 2g prehospital administration
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sion of patients with concomitant trauma not isolated to the of TXA resulted in a significantly improved 28-day mortal-
head prevented a definitive conclusion from the investigators. ity of 18% compared to 28% mortality in the 1g TXA bolus
In 2014, a lack of evidence of benefit was cited as rationale for + 1g maintenance infusion group and 28% mortality in the
not giving TXA in TBI. A meta-analysis published the same placebo group. For 2g TXA bolus vs placebo, the difference in
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year noted a “statistically significant reduction in ICH progres- outcome was highly significant for those diagnosed with ICH
sion with TXA and non-statistically significant improvement (p = .0035). The 1g infusion followed by 1g over 8 hours was
of clinical outcomes in ED patients with TBI.” Dosing was 1g not different from placebo. For the entire cohort (identified
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over 10 minutes followed by an additional 1g over eight hours, prehospital based on criteria of GCS 3-12, one or two reactive
which is the same as the CRASH-2 trial and the current TCCC pupils and SBP ≥ 90), there was no negative effect of giving
Guidelines. As recently as 2016, there was a continued call for TXA for potential ICH based on both mortality and throm-
research to investigate optimal TXA dosing in TBI. Several botic complications. 44
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studies have examined the use of TXA in patients with identi-
fied intracranial hemorrhage (ICH), but these studies were not Should a TBI Indication for TXA Be Added to the
designed to treat all TBIs and the TXA was given once the ICH TXA Recommendations in the TCCC Guidelines and
was identified on CT (not prehospital). Dosing was the same the Dose Increased to 2 Grams?
as the current TCCC Guidelines. In two studies that found no In addition to previously discussed work supporting a 2g dose
benefit from TXA administration to TBI patients, one made no for TXA in TBI, there is evidence of a 1g dose not being suffi-
mention of the time of administration and in the other only cient in severe trauma. Grassin-Delyle et al noted that a 1g
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