Page 140 - JSOM Spring 2023

Clinical use of tranexamic acid: evidences and The risk of thromboembolic events with early intravenous
controversies 2 and 4g bolus dosing of tranexamic acid compared
Maria J Colomina, Laura Contreras, Patricia Guilabert, Maylin to placebo in patients with severe traumatic bleeding:
Koo, Esther M Ndez, Antoni Sabate a secondary analysis of a randomized, double-blind,
placebo-controlled, single-center trial
Braz J Anesthesiol. 2022;72(6):795–812.
Philip C. Spinella, Kelly Bochicchio, Kimberly A Thomas, Amanda
Tranexamic acid (TXA) significantly reduces blood loss in a wide Staudt, Susan M Shea, Anthony E Pusateri, Douglas Schuerer, Jer-
range of surgical procedures and improves survival rates in obstet- rold H Levy, Andrew P Cap, Grant Bochicchio
ric and trauma patients with severe bleeding. Although it mainly
acts as a fibrinolysis inhibitor, it also has an anti-inflammatory Transfusion. 2022;62 Suppl 1:S139–S150.
effect, and may help attenuate the systemic inflammatory response Background: Screening for the risk of thromboembolism (TE) due
syndrome found in some cardiac surgery patients. However, the to tranexamic acid (TXA) in patients with severe traumatic injury
administration of high doses of TXA has been associated with sei- has not been performed in randomized clinical trials. Our objec-
zures and other adverse effects that increase the cost of care, and tive was to determine if TXA dose was independently associated
the administration of TXA to reduce perioperative bleeding needs with thromboembolism. Methods: This is a secondary analysis
to be standardized. Tranexamic acid is generally well tolerated, of a single-center, double-blinded, randomized controlled trial
and most adverse reactions are considered mild or moderate. Se- comparing placebo to a 2g or 4g intravenous TXA bolus dose
vere events are rare in clinical trials, and literature reviews have in trauma patients with severe injury. We used multivariable dis-
shown TXA to be safe in several different surgical procedures. crete-time Cox regression models to identify associations with risk
However, after many years of experience with TXA in various for thromboembolic events within 30 days post-enrollment. Event
fields, such as orthopedic surgery, clinicians are now querying curves were created using discrete-time Cox regression. Results:
whether the dosage, route and interval of administration currently There were 50 patients in the placebo group, 49 in the 2g, and
used and the methods used to control and analyze the antifibri- 50 in the 4g TXA group. In adjusted analyses for thromboembo-
nolytic mechanism of TXA are really optimal. These issues need lism, a 2g dose of TXA had a hazard ratio (HR, 95% confidence
to be evaluated and reviewed using the latest evidence to improve interval [CI]) of 3.20 (1.12–9.11) (p = .029), and a 4g dose of
the safety and effectiveness of TXA in treating intracranial hemor- TXA had an HR (95% CI) of 5.33 (1.94–14.63) (p = .001). Event
rhage and bleeding in procedures such as liver transplantation and curves demonstrated a higher probability of thromboembolism
cardiac, trauma, and obstetric surgery. for both doses of TXA compared to placebo. Other parameters in-
dependently associated with thromboembolism include time from
Pharmacokinetics of intramuscular tranexamic acid in injury to TXA administration, body mass index, and total blood
bleeding trauma patients: a clinical trial products transfused. Discussion: In patients with severe traumatic
Stanislas Grassin-Delyle, Haleema Shakur-Still, Roberto Picetti, injury, there was a dose-dependent increase in the risk of at least
Lauren Frimley, Heather Jarman, Ross Davenport, William Mc- one thromboembolic event with TXA. TXA should not be with-
Guinness, Phil Moss, Jason Pott, Nigel Tai, Elodie Lamy, Saïk held, but thromboembolism screening should be considered for
Urien, Danielle Prowse, Andrew Thayne, Catherine Gilliam, Har- patients receiving a dose of at least 2g TXA intravenously for trau-
vey Pynn, Ian Roberts matic hemorrhage.
Br J Anaesth. 2021;126(1):201–209. Effect of out-of-hospital tranexamic acid vs placebo on
Background: Intravenous tranexamic acid (TXA) reduces bleed- 6-month functional neurologic outcomes in patients with
ing deaths after injury and childbirth. It is most effective when moderate or severe traumatic brain injury
given early. In many countries, pre-hospital care is provided by Susan E Rowell, MD, MBA; Eric N Meier, MS; Barbara McKnight,
people who cannot give IV injections. We examined the phar- PhD; Delores Kannas, RN, MS, MHA; Susanne May, PhD; Kel-
macokinetics of intramuscular TXA in bleeding trauma patients. lie Sheehan, RN; Eileen M Bulger, MD; Ahamed H Idris, MD;
Methods: We conducted an open-label pharmacokinetic study Jim Christenson, MD; Laurie J Morrison, MD; Ralph J Frascone,
in two UK hospitals. Thirty bleeding trauma patients received a MD; Patrick L Bosarge, MD; M Riccardo Colella, DO, MPH; Jay
loading dose of TXA 1g IV, as per guidelines. The second TXA Johannigman, MD; Bryan A Cotton, MD; Jeannie Callum, MD;
dose was given as two 5mL (0.5g each) IM injections. We col- Jason McMullan, MD; David J Dries, MD; Brian Tibbs, MD; Neal
lected blood at intervals and monitored injection sites. We mea- J Richmond, MD; Myron L Weisfeldt, MD; John M Tallon, MD,
sured TXA concentrations using liquid chromatography coupled MSc; John S Garrett, MD; Martin D Zielinski, MD; Tom P Auf-
to mass spectrometry. We assessed the concentration time course derheide, MD; Rajesh R Gandhi, MD, PhD; Rob Schlamp; Bryce
using non-linear mixed-effect models with age, sex, ethnicity, RH Robinson, MD; Jonathan Jui, MD, MPH; Lauren Klein, MD,
body weight, type of injury, signs of shock, and glomerular fil- MS; Sandro Rizoli, MD; Mark Gamber, DO; Michael Fleming,
tration rate as possible covariates. Results: Intramuscular TXA BA; Jun Hwang, MS; Laura E Vincent, RN; Carolyn Williams,
was well tolerated with only mild injection site reactions. A RN; Audrey Hendrickson, MPH; Robert Simonson, DO; Patricia
two-compartment open model with first-order absorption and Klotz, RN; George Sopko, MD; William Witham, MD; Michael
elimination best described the data. For a 70-kg patient, aged Ferrara, MS; Martin A Schreiber, MD
44 yr without signs of shock, the population estimates were 1.94 JAMA. 2020;324(10):961–974.
h for IM absorption constant, 0.77 for IM bioavailability, 7.1L
–1
–1
–1
h for elimination clearance, 11.7L h for intercompartmental Importance: Traumatic brain injury (TBI) is the leading cause
clearance, 16.1L volume of central compartment, and 9.4L vol- of death and disability due to trauma. Early administration of
ume of the peripheral compartment. The time to reach therapeutic tranexamic acid may benefit patients with TBI. Objective: To deter-
concentrations (5 or 10mg L ) after a single intramuscular TXA mine whether tranexamic acid treatment initiated in the out-of-hos-
–1
1g injection is 4 or 11 min, with the time above these concen- pital setting within 2 hours of injury improves neurologic outcome
trations being 10 or 5.6 h, respectively. Conclusions: In bleeding in patients with moderate or severe TBI. Design, setting, and par-
trauma patients, intramuscular TXA is well tolerated and rapidly ticipants: Multicenter, double-blinded, randomized clinical trial at
absorbed. 20 trauma centers and 39 emergency medical services agencies in
the US and Canada from May 2015 to November 2017. Eligible
138 | JSOM Volume 23, Edition 1 / Spring 2023