Journal of Medical Sciences

REVIEW ARTICLE
Year
: 2022  |  Volume : 42  |  Issue : 3  |  Page : 103--108

Potential utility of tranexamic acid in combat trauma


Shalendra Singh, George Cherian Ambooken, Venigalla Sri Krishna 
 Department of Anaesthesiology and Critical Care, Armed Forces Medical College, Pune, Maharashtra, India

Correspondence Address:
Prof. Shalendra Singh
Department of Anaesthesiology and Critical Care, Armed Forces Medical College, Pune - 411 040, Maharashtra
India

Abstract

Tranexamic acid (TXA) lessens surgical bleeding and reduces mortality in patients with traumatic hemorrhage. Hemorrhage is common in combat zones and is one of the most common causes of mortality in a war scenario. The management of hemorrhage involves early arrest/temporization of ongoing bleed and restoration of blood volume to restore physiological stability as soon as possible. TXA by its antifibrinolytic action decreases blood loss, thus circumventing the requirement of massive crystalloid resuscitation, in turn an important causative factor for acute traumatic coagulopathy. Currently, TXA is recommended in acute hemorrhage worldwide; thus, its use in the combat scenario needs to be conceptualized by the primary caregivers. This conceptualization will be discussed in detail in this review article.



How to cite this article:
Singh S, Ambooken GC, Krishna VS. Potential utility of tranexamic acid in combat trauma.J Med Sci 2022;42:103-108


How to cite this URL:
Singh S, Ambooken GC, Krishna VS. Potential utility of tranexamic acid in combat trauma. J Med Sci [serial online] 2022 [cited 2022 Jul 2 ];42:103-108
Available from: https://www.jmedscindmc.com/text.asp?2022/42/3/103/329725


Full Text



 Introduction



Prehospital resuscitation strategies have been identified to be a major cause of survival in patients with ongoing hemorrhage. Combat battle injuries patients often have massive hemorrhage leading to exhaustion of physiological reserves before their arrival to forward surgical centers (FSC). Resuscitation before arrival at FSC limits the physiological derangement. Tranexamic acid (TXA) is an antifibrinolytic drug that has found widespread use in the control of hemorrhagic conditions, including a variety of surgeries such as orthopedic, cardiac, obstetric, and spinal surgeries.[1],[2],[3],[4],[5] Recently, however, its use in trauma patients has garnered attention, with various trials finding a potential benefit of using TXA in the trauma victim. For example, the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2 (CRASH-2) trial showed a definite reduction in the all-cause mortality from 16.0% to 14.5% and the bleeding-related deaths from 5.7% to 4.9% when TXA was administered within three hours of injury.[6] This trial in turn led to greater use and study of the drug in trauma patients in a combat setting, with the British and US militaries incorporating the use of TXA into its combat casualty guidelines. Recently, the Clinical Randomization of an Antifibrinolytic in Significant Head Injury (CRASH-3) trial revealed that TXA could save one in five people who would have died following a mild or moderate head injury.[7] In this article, we aim to consolidate the available information on the use of TXA in combat casualty care, which will in turn aid in developing a standard of care in combat trauma patients at FSC or forward locations.

 Methods



To detect all available studies on words TXA and combat trauma care, we conducted a systematic literature search in PubMed, Ovid, Medline, and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The last search was performed on August 11, 2020, with no language restriction, using the following terms in all possible combinations: TXA, COMBAT, COMBAT CARE, TRAUMA, BLEEDING, HEMORRHAGE, FORWARD AREA, WAR, AND RESUSCITATION. Moreover, the lists of the bibliographic references of all included articles were manually screened. In case of missing data among studies fulfilling the inclusion criteria, the authors were contacted by E-mail to try to claim the original data. One author (George Cherian Ambooken) analyzed each article and separately performed the extraction of data. In case of disagreement, another author (Venigalla Sri Krishna) was contacted. Discrepancies were resolved by consensus. Overall, selection results showed in the PRISMA flow-chart [Figure 1]. According to a predetermined protocol, all studies reporting data about TXA and combat trauma care were included in the study. Reviews and articles on animal models were excluded from the study. Overall, we included in the analysis all studies providing data about TXA in hemorrhage, the use of TXA during active bleeding, or any complication due to TXA. Studies reporting on the autopsy evidence TXA-induced thrombosis events were also included in the study.{Figure 1}

 About Tranexamic Acid



TXA is a synthetic derivative of the amino acid lysine and at low doses, acts by competitively binding to the five lysine binding sites on plasminogen.[8] This competitive inhibition, therefore, prevents plasmin formation, which is a serine protease responsible for the dissolution of fibrin in fibrin clots [Figure 2]. At higher concentrations, TXA also shows a direct noncompetitive inhibition of plasmin activity. It is also thought to improve platelet function in certain cases by inhibiting plasmin-mediated activation of complement, monocytes, and neutrophils.{Figure 2}

TXA can be administered through the oral or the intravenous route.[9] The oral dose is 15–25 mg/kg 2–3 times/day.[10] The intravenous dosage is typically 0.5–1 g by slow injection 3 times/day.[11] Alternatively, the initial dose can be followed by an infusion of 25–50 mg/kg over 24 h.[12] However, these dosing limits are directives, and a meta-analysis of randomized trials in 49 studies with 10,591 patients in all kinds of cardiac surgeries shows low-dose intravenous infusion was the most preferable delivery method and as effective as high-dose regimen in reducing transfusion rate.[13] TXA is generally well tolerated, with few side effects. However, a theoretical risk of thromboembolic phenomena has traditionally led to moderation in its use, even though recent studies have failed to show increased thromboembolism risk.[14],[15] In addition, seizure activity following TXA use has also been described, though the exact mechanism for the same remains unexplained.[16] However, this effect has only been found with doses above that used in trauma and is common in patients undergoing cardiac surgeries.[17]

 Indications



The accepted indications for TXA as approved by the US Food and Drug Administration remain limited to intravenous administration in hemophilia patients to prevent hemorrhage during tooth extraction and to reduce the need for coagulation factor replacement, and orally for reducing bleeding in menorrhagia.[18] While the usage of TXA for all other indications remains “off-label,” this has not prevented the widespread use of TXA over the past two decades. In addition, following the withdrawal of aprotinin from the market due to concerns regarding its cardiovascular and renal safety, the use of TXA in elective surgery has increased multi-fold. TXA is now in widespread use in surgeries where excess blood loss is expected or hyperfibrinolysis is an established feature, such as obstetric surgeries, cardiac surgeries, major joint arthroplasties, spinal surgeries, and hepatic surgeries.[1],[2],[3],[4],[5],[19] Apart from the above-mentioned elective and emergency surgeries, TXA is of significant use in trauma cases.

 Tranexamic Acid in Trauma Care



The antifibrinolytic action of TXA garnered interest for its potential benefit in trauma, culminating in the conduct of the CRASH trials. The CRASH-2 trial, a randomized placebo-controlled trial carried out in 274 hospitals across 40 countries randomized over 20,000 trauma patients presenting within 8 h of the initial injury to receive either TXA (1 g loading dose followed by 1 g over 8 h intravenously) or placebo, while excluding those who had a clear indication or contraindication to the use of TXA.[6]

The CRASH-2 trial demonstrated a statistically significant reduction in all-cause mortality of 1.5%, with the greatest benefit being in those treated within the first 3 h of injury. Further analysis of the subgroups identified that this reduction in mortality could be attributed to a reduction in bleeding episodes. However, the CRASH-2 trial also showed an unexplained increase in mortality in trauma victims treated with TXA after 8 h of the initial injury, thereby encouraging caution in its indiscriminate use in all trauma patients after 8 h of injury.[20]

 Tranexamic Acid in Battlefield



While the CRASH trials encouraged the use of TXA in trauma patients and heralded more general interest in TXA, its use in the military setting was limited by the fact that military trauma varies significantly from civilian trauma, not least in the fact that military trauma occurs in a resource-strapped setting. With the CRASH study being conducted primarily in well-equipped hospitals, the data obtained could not be extrapolated to assess the risk/benefit in exsanguinating patients on the battlefield. This prompted the Military Application of TXA in Trauma Emergency Resuscitation (MATTERs) study, which showed promising results for the use of TXA in combat trauma as well.

The MATTERs study was a retrospective observational study carried out by assessing 896 combat trauma patients who had received a transfusion of at least 1 unit of packed red blood cells (PRBCs), of which 293 received TXA within the 1st h of injury. The study measured the mortality of these patients at 24 h, 48 h, and 30 days, apart from analyzing if TXA administration affected the rate of thromboembolic complications. The study showed a definite benefit in the administration of TXA in combat trauma patients within 1 h of injury in those patients who received TXA had lower 24 h mortality (9.6% vs. 12.4%), 48-hour mortality (11.3 vs. 18.9%), and in-hospital mortality (17.4 vs. 23.9%) as compared to patients who had not received TXA.[21] This benefit was even more pronounced in patients who also simultaneously received a massive transfusion (defined as transfusion of 10 units of PRBCs or more). The MATTERs study also identified a Glasgow Coma Scale (GCS) score of <8, the presence of hypotension and/or coagulopathy on admission to be independently associated with mortality. In the subgroup analysis of patients who had received a massive transfusion, a GCS of <8 or an injury severity score (ISS) of more than 15 were found to be associated with mortality, whereas TXA administration was associated with survival. In addition, the study also showed that TXA administration had no association with deep vein thrombosis or pulmonary thromboembolism.

To further the knowledge obtained from the MATTERs study, the MATTERs II study was conducted in 2013. This study quantified the impact of the addition of cryoprecipitate to TXA, and measured its effect on survival in combat trauma. The study showed that despite the patients receiving both TXA and cryoprecipitate being more injured, with the consequent requirement of greater amounts of PRBCs, the mortality was least in the cryoprecipitate + TXA group (11.6%), as compared to the TXA (18.2%), cryoprecipitate (21.4%), or no cryoprecipitate/TXA (23.6%) groups. The MATTERs II study, therefore, showed a definitive advantage for the addition of cryoprecipitate with TXA in the management of the severely injured combat casualty with a 62% relative reduction in mortality in this group.[22]

However, in 2014, Valle et al. refuted the hypothesis that early routine use of TXA reduces mortality in a subset of the most critically injured trauma intensive care unit patients, and showed an increased rather than reduced mortality in patients receiving routine early administration of TXA.[23] However, this study was limited by a small sample size, and was conducted in civilian settings. Howard et al. have conducted the largest study on TXA use in a combat trauma population to date. The retrospective, observational study of 3773 casualties showed results varying significantly from the previous studies conducted exclusively in such a population. This study showed no significant association between TXA administration and mortality, except in a small subset of casualties with multiple amputation injuries.[24] While the findings of the study also leaned toward showing a benefit for TXA administration while measured in terms of mortality, the same association could not be proved owing to a lack of statistical power. A GCS of <8, an ISS of >15, and systolic blood pressure of <90 mmHg on arrival were found to be strong predictors of mortality, in sync with the findings of the MATTERs study. However, in contrast to the MATTERs I and II studies, TXA was found to increase the chances of pulmonary thromboembolism and deep vein thrombosis in this population, albeit not in the propensity-matched sample.

Apart from the above-mentioned large-scale studies, other specific studies have also been conducted to study specific effects or subgroups. Lipsky et al. studied the experience of the Israeli Defense Forces in the administration of TXA in the prehospital setting, using a sample of 40 patients, and reported that no adverse outcomes could reasonably be attributed to TXA administration.[25] This favorable safety profile combined with the fact that TXA administration was likely to be most beneficial when administered early after injury prompted them to recommend that TXA may be made available to advanced life support providers in the prehospital setting. The PED-TRAX study evaluated all pediatric trauma admissions to a NATO Role 3 hospital in Afghanistan. A total of 766 injured patients aged 18 or younger formed part of the study, of which only 9% (66 patients) received TXA. This study showed that TXA use was associated with significantly decreased mortality in all patients, including the subgroups of severely injured and transfused groups in a propensity-matched sample.[26] No adverse effects relating to TXA use could be identified in the study. A specific study to evaluate the use of TXA in the military setting also showed that while military personnel tended to miss fewer opportunities to administer TXA in cases where it could possibly be of benefit, they also showed a tendency for overuse of the medication as well, thereby prompting caution in its use.[27]

 Concept of Carrying Tranexamic Acid Vials Into Forward Areas



Timing of the giving TXA is critical as it will likely have the most impact in achieving hemostasis for “successful outcomes.” The above-noted studies have revealed that TXA has to be given as soon as possible to a bleeding patient in a combat zone. This implies every medical officer/nursing assistant should carry TXA and inject TXA Vial in the first bottle of intravenous crystalloid to stop ongoing bleeding in forward areas.

 Controversies Regarding Tranexamic Acid and Increased Thrombotic Risk



Due to its mechanism of action, there was concern regarding the use of TXA causing the patient to be at an increased risk of thrombotic events. However, a systematic review of 22 randomized control trials by Chornenki et al.[28] found that there was no increased risk of thrombotic events in nonsurgical patients receiving TXA. Similar findings have also been found in other systematic reviews and meta-analyses.[29],[30]

 Conclusion



While most available literature agrees that the early use of TXA in combat trauma casualties is favorably associated with a decrease in mortality, the largest such study could not prove a statistical significance to this association. In addition, the available literature showed contradictory results on the incidence of adverse effects, which could be attributable to the administration of TXA. However, this possible increase in the incidence of pulmonary thromboembolism or deep vein thrombosis could be offset by the mortality benefit to the early administration of TXA in combat trauma patients. The sole study conducted on TXA administration in pediatric patients showed a definite benefit in the early administration of the same in severely injured patients. Based on the currently available body of evidence, the US Army Joint Theater Trauma System Damage Control Resuscitation/Clinical Practice Guidelines has presently advised that early use of TXA should be considered in any patient who is likely to require a massive transfusion and that if being administered, TXA should be administered within 3 h of injury. However, although the CRASH-2 trial in 2002 and the CRASH-3 trial in 2019 revealed that TXA could lead to a definite reduction in all-cause of mortality following traumatic bleeding, larger studies are required before a consensus can be reached on the use of TXA in the management of a combat casualty.

In our opinion, based on present literature, controlling hemorrhage with hemostatic dressings or tourniquet, using early TXA in the first intravenous fluid given, with the intention of minimizing overall infused fluid volume and preventing hypothermia along with evacuating the patient remains the key for a successful outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Reed MR, Woolley LC. Uses of tranexamic acid. Contin Educ Anaesth Crit Care Pain 2015;15:32-7.
2Huang F, Wu D, Ma G, Yin Z, Wang Q. The use of tranexamic acid to reduce blood loss and transfusion in major orthopedic surgery: A meta-analysis. J Surg Res 2014;186:318-27.
3Pacheco LD, Hankins GD, Saad AF, Costantine MM, Chiossi G, Saade GR. Tranexamic acid for the management of obstetric hemorrhage. Obstet Gynecol 2017;130:765-9.
4Sethna NF, Zurakowski D, Brustowicz RM, Bacsik J, Sullivan LJ, Shapiro F. Tranexamic acid reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery. Anesthesiology 2005;102:727-32.
5Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med 2017;376:136-48.
6Perel P, Al-Shahi Salman R, Kawahara T, Morris Z, Prieto-Merino D, Roberts I, et al. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: The effect of tranexamic acid in traumatic brain injury – A nested randomised, placebo-controlled trial. Health Technol Assess 2012;16:i-54.
7CRASH-3 Trial Collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): A randomised, placebo-controlled trial. Lancet 2019;394:1713-23.
8Dunn CJ, Goa KL. Tranexamic acid: A review of its use in surgery and other indications. Drugs 1999;57:1005-32.
9Grassin-Delyle S, Semeraro M, Foissac F, Bouazza N, Shakur-Still H, Roberts I, et al. Tranexamic acid through intravenous, intramuscular and oral routes: An individual participant data meta-analysis of pharmacokinetic studies in healthy volunteers. Fundam Clin Pharmacol 2019;33:670-8.
10Pabinger I, Fries D, Schöchl H, Streif W, Toller W. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr 2017;129:303-16.
11Gupta B. Is irrational use of tranexamic acid justified in anesthesia practice? Korean J Anesthesiol 2018;71:237-8.
12HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): An international randomised, double-blind, placebo-controlled trial. Lancet 2020;395:1927-36.
13Guo J, Gao X, Ma Y, Lv H, Hu W, Zhang S, et al. Different dose regimes and administration methods of tranexamic acid in cardiac surgery: A meta-analysis of randomized trials. BMC Anesthesiol 2019;19:129.
14Nishihara S, Hamada M. Does tranexamic acid alter the risk of thromboembolism after total hip arthroplasty in the absence of routine chemical thromboprophylaxis? Bone Joint J 2015;97-B:458-62.
15Ahmadzia HK, Hynds EB, Amdur RL, Gimovsky AC, James AH, Luban NL. National trends in tranexamic acid use in the peripartum period, 2015-2019. J Thromb Thrombolysis 2020;50:746-52.
16Lecker I, Wang DS, Whissell PD, Avramescu S, Mazer CD, Orser BA. Tranexamic acid-associated seizures: Causes and treatment. Ann Neurol 2016;79:18-26.
17Lecker I, Orser BA, Mazer CD. “Seizing” the opportunity to understand antifibrinolytic drugs. Can J Anaesth 2012;59:1-5.
18Chauncey JM, Wieters JS. Tranexamic acid. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. https://www.ncbi.nlm.nih.gov/books/NBK532909/. [Last updated on 2021 Mar 02].
19Karanicolas PJ, Lin Y, Tarshis J, Law CH, Coburn NG, Hallet J, et al. Major liver resection, systemic fibrinolytic activity, and the impact of tranexamic acid. HPB (Oxford) 2016;18:991-9.
20Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. The CRASH-2 trial: A randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess 2013;17:1-79.
21Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg 2012;147:113-9.
22Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: Findings from the MATTERs II Study. JAMA Surg 2013;148:218-25.
23Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, Livingstone AS, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg 2014;76:1373-8.
24Howard JT, Stockinger ZT, Cap AP, Bailey JA, Gross KR. Military use of tranexamic acid in combat trauma: Does it matter? J Trauma Acute Care Surg 2017;83:579-88.
25Lipsky AM, Abramovich A, Nadler R, Feinstein U, Shaked G, Kreiss Y, et al. Tranexamic acid in the prehospital setting: Israel Defense Forces' initial experience. Injury 2014;45:66-70.
26Eckert MJ, Wertin TM, Tyner SD, Nelson DW, Izenberg S, Martin MJ. Tranexamic acid administration to pediatric trauma patients in a combat setting: The pediatric trauma and tranexamic acid study (PED-TRAX). J Trauma Acute Care Surg 2014;77:852-8.
27Johnston LR, Rodriguez CJ, Elster EA, Bradley MJ. Evaluation of military use of tranexamic acid and associated thromboembolic events. JAMA Surg 2018;153:169-75.
28Chornenki NL, Um KJ, Mendoza PA, Samienezhad A, Swarup V, Chai-Adisaksopha C, et al. Risk of venous and arterial thrombosis in non-surgical patients receiving systemic tranexamic acid: A systematic review and meta-analysis. Thromb Res 2019;179:81-6.
29Relke N, Chornenki NL, Sholzberg M. Tranexamic acid evidence and controversies: An illustrated review. Res Pract Thromb Haemost 2021;5:e12546.
30Taeuber I, Weibel S, Herrmann E, Neef V, Schlesinger T, Kranke P, et al. Association of intravenous tranexamic acid with thromboembolic events and mortality: A systematic review, meta-analysis, and meta-regression. JAMA Surg 2021;156:e210884.