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Resident Eagle: Nonmechanical Hemostasis in Trauma Care
Resident Eagle is a monthly column profiling the work of top EMS physicians and medical directors from the Metropolitan EMS Medical Directors Global Alliance (the "Eagles"), who represent America’s largest and key international cities. Tentative dates for Gathering of Eagles 2021: June 14–18, Hollywood, Fla. For more see useagles.org.
Modern trauma systems were created more than a half century ago to enable severely injured patients to reach a facility where surgeons were standing by around-the-clock ready to rapidly achieve anatomical hemostasis (physical bleeding control) for internal hemorrhage and/or evacuate blood and control further bleeding within the intracranial vault.1
Time is of the essence. Physically clamping and repairing damaged blood vessels within the chest, abdomen, or skull must be achieved before exsanguination or fatal CNS compromise. A person’s own blood is equipped with optimal clotting factors and functioning platelets. It is the ultimate medium for sustaining human life minute to minute with delivery of oxygen to vital organs. While timely transfusions can be useful, optimally one’s own blood needs to be kept within one’s own body.
Over the past several years, it has been recognized that trauma centers are just one step to save more lives. Inherently, even without the need for an extended extrication, significant time will elapse before surgical intervention can be accomplished when the bleeding patient has to be transported from a trauma scene. As a result there has been a renewed emphasis on providing prehospital bleeding control with tourniquets, especially with civilian Stop the Bleed programs.2,3 Other external pressure devices, intra-arterial catheters (REBOA), and intraperitoneal foam products have also been proposed, but of particular note, the concept of nonmechanical (nonanatomical) hemostasis has also taken root.4
Nonanatomical Hemostasis
For the past two decades, the concept of using techniques that would assist in promoting physiological hemostasis (enhanced blood clotting) has gained traction through the introduction of clotting stimulants or clot-enhancing agents.2
Topical clot-stimulating agents or dressings, usually delivered in a gauze form, are typically used to pack deeper bleeding wounds for which direct pressure or tourniquets have not been feasible or sufficient to control external bleeding.2 There are now multiple available products, and most military and civilian medics are familiar with this adjunct to bleeding control.
More recently, while not yet widely established, mechanisms have now been developed to bring plasma and even low-titer O-positive whole blood to the prehospital setting.5,6,8–10 Such programs require a multifaceted coordination of hospitals, blood banks, regional trauma councils, and targeted donor pools, but they may also provide an important role in mitigation of preoperative bleeding.6,8–10 In the past, post-traumatic hypotension from blood loss was treated with intravenous isotonic fluids or colloids in an attempt to support blood pressure. However, these interventions were eventually found to worsen the situation through dissolution of soft clots and disruption of the glycocalyx protecting the vascular endothelium.7–11
In contrast to crystalloids, blood products help mitigate the accompanying coagulopathy seen in severe trauma. Use of both plasma and whole blood in the prehospital setting has been found to be lifesaving without significantly increased risk of complications.8–11 The components of whole blood are not only protective of the vascular endothelium; they can even facilitate its repair.5,8–11 Beyond oxygen-carrying capacity, whole blood also has the benefit of infusing relatively normal clotting capacity versus other blood products.5,7,12
Prehospital blood infusion is clearly a positive step forward in trauma care, though it does involve specialized equipment, logistics, and systemwide coordination. It still must be recognized that whole blood and plasma do not definitively control active bleeding, nor do they entirely manage the consequences of intracranial bleeding in traumatic brain injury (TBI).
The Rationale for TXA in Trauma
One medication used since the 1960s to promote hemostasis has been tranexamic acid (TXA). TXA has been used topically for severe nosebleeds or infused parenterally for menorrhagia, post-partum hemorrhage, and many elective surgeries for which it has reduced blood loss and the need for transfusion.13
TXA was originally developed as an analog of the amino acid lysine that could attach to lysine binding sites on plasminogen.13,14 It is also an inhibitor of native tissue plasminogen activator (tPA).14 These actions inhibit plasmin formation, displacing plasminogen from the surface of fibrin, which impairs fibrinolysis, the body’s normal process of dissolving clots. This maintains a more coagulable state in the bloodstream.
TXA may also have a powerful anti-inflammatory role because of its ability to mitigate excess generation of certain circulating inflammatory factors, such as the cytokines, cachexin, and interleukin-6 (IL-6).15 Likewise, it inhibits the pro-inflammatory pathways of Poly (ADP-ribose) polymerase-1 (PARP-1) and nuclear factor kappaB. In addition, through a plasmin-based mechanism, TXA has the ability to decrease endothelial permeability and therefore reduce brain edema. All these actions contribute to the complex nature of the actions of TXA.13–15
Accordingly, more than a decade ago, a multicenter study largely conducted in Europe examined the use of TXA for trauma patients. TXA was provided as an infusion for patients with presumptive internal bleeding (injury with hypotension). The study, CRASH-2, examined the use of one gram of TXA infused as a bolus as soon as possible, then an additional gram infused over several hours.16 The concept for this approach was adopted from prior clinical use in certain neurovascular and cardiovascular surgeries, where a gram of TXA was given as a bolus and then another continued as a maintenance infusion during the surgery to help control the bleeding.13,16
CRASH-2 was an ambitious project that involved 274 hospitals and 20,211 patients in 40 countries. Taken at face value, CRASH-2 overall showed TXA saved lives, but most strikingly, the earlier it was administered, the better the outcome. In addition, TXA was relatively inexpensive and easy to administer.16,17 More important, if the TXA was not given for several hours after injury, the outcome actually appeared to be worse. Presumptively, poorer outcomes with late infusion in CRASH-2 may have reflected that patients had already progressed to a less salvageable state or alternatively that the ongoing eight-hour follow-up infusions were given when bleeding should have already been controlled. By that time the risk of more complications would clearly outweigh benefits.
Despite the positive results, the study incurred some critiques that included concerns about the heterogeneity of the study populations, trauma systems, and data collection across 40 countries in Africa, South America, Europe, and North America. Also, despite the significant differences generated by the exceptionally large numbers studied, relative differences in mortality (4.9 vs. 5.7%) were relatively small, and other investigators’ concern over identifying complication risks within subgroups, including deep vein thrombosis and seizures, still remained.18–21 A decade later there has been some lingering ambivalence and even skepticism, with many investigators urging caution.19
Regardless of one’s viewpoint, there is one important conceptual paradigm to appreciate from CRASH-2: Accepting the findings overall, it emphasizes that a medication, procedure, or device should not be seen in terms of a binary outcome (i.e., effective or not effective). Instead, the findings indicate the intervention can have great value depending on when or how it is used.18 At the same time, the same intervention could be harmful if used too late or improperly. CRASH-2 demonstrated that principle quite well, a concept that is central to the theme of evidence-based medicine.16,18
Some have argued the use of TXA should be guided by blood assay techniques such as thromboelastography (TEG).22,23 TEG depicts a global evaluation of clot formation. It identifies clot strength and ease of degradation, illustrating the interaction and function (or dysfunction) of clotting factors, platelets, and plasma components. If indicated, TXA would be given as indicated by TEG findings.22,23 However, TEG is performed in hospital, implying further delays before giving TXA, and recently published data indicate prehospital infusion of TXA does not create measurable TEG alterations.24 That finding might suggest either TEG insensitivity or that the mechanism of TXA efficacy is not simply related to coagulation effects.15 Also, coagulopathies may have progressed too far by that time for TXA to change outcomes.
In the second part of this series, we will fast-forward to a review of the past 12 months, in which two game-changing clinical trials were published that have now reinforced the growing value of TXA in trauma care.
References
1. American College of Surgeons. Part 1: A Brief History of Trauma Systems, www.facs.org/quality-programs/trauma/tqp/systems-programs/trauma-series/part-i.
2. Williamson K, Ramesh R. Grabinsky A. Advances in prehospital trauma care. Int J Crit Ill Inj Sci, 2011; 1: 44–50.
3. Joint Committee to Create a National Policy to Enhance Survivability from Intentional Mass Casualty and Active Shooter Events. The Hartford Consensus III: implementation of bleeding control. Bull Am Coll Surg, 2015; 100: 20–6.
4. Matsumura Y, Matsumoto J, Kondo H, et al. Early arterial access for REBOA is related to survival outcome in trauma. J Trauma Acute Care Surg, 2018 Sep; 85: 507–11.
5. Black J, Pierce V, Kerby J, Holcomb J. The evolution of blood transfusion in the trauma patient: whole blood has come full circle. Sem Thromb Hemost, 2020 Mar; 46: 215–20.
6. Pepe PE, Roach JP, Winckler CJ. State of the art review: Prehospital resuscitation with low titer O+ whole blood by civilian EMS teams—rationale and evolving strategies for use. In: Vincent JL (ed.), 2020 Annual Update in Intensive Care and Emergency Medicine. Berlin: Springer International Publishing, 2020; pp. 366–76.
7. Pepe PE. Chapter 6: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. In: Cohn S, Feinstein A (eds.), 50 Landmark Papers Every Trauma Surgeon Should Know. CRC Press, 2020; pp.23–9.
8. Spinella PC, Pidcoke HF, Strandenes G, et al. Whole blood for hemostatic resuscitation of major bleeding. Transfusion, 2016; 56 Suppl 2: S190–S202.
9. Sperry JL, Guyette FX, Brown JB, et al. Prehospital plasma during air medical transport in trauma patients at risk of hemorrhagic shock. N Engl J Med, 2018; 379: 315–26.
10. Shackelford SA, del Junco DJ, Powell‐Dunford N, et al. Association of prehospital blood product transfusion during medical evacuation of combat casualties in Afghanistan with acute and 30‐day survival. JAMA, 2017; 318: 1,581–91.
11. Diebel ME, Diebel LN, Liberati DM. Protective effects of plasma products on the endothelial-glycocalyx barrier following trauma-hemorrhagic shock: Is sphingosine-1 phosphate responsible? J Trauma Acute Care Surg, 2019; 87(5): 1,061–9.
12. Arya RC, Wander GS, Gupta P. Blood component therapy: which, when and how much? J Anaesthesiol Clin Pharmacol, 2011 Apr–Jun; 27: 278–84.
13. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ, 2012; 344: e3054.
14. Teng Y, Feng C, Yunen L, Hongxu J, Gao Y, Li T. Anti-inflammatory effect of tranexamic acid against trauma-hemorrhagic shock-induced acute lung injury in rats. Exp Anim, 2018; 67: 313–20.
15. Wang D, Luo ZY, Yu ZP, et al. The antifibrinolytic and anti-inflammatory effects of multiple doses of oral tranexamic acid in total knee arthroplasty patients: a randomized controlled trial. J Thromb Haemost, 2018; 16: 2,442–53.
16. CRASH-2 Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet, 2010 Jul 10; 376: 1,713–23.
17. Guerrerio C, Cairns J, Perel P, Shakur H, Roberts I on behalf of the CRASH-2 trial investigators. Cost-effectiveness analysis of administering tranexamic acid the bleeding trauma patients using evidence from the CRASH-2 trial. PLoS One, 2011; 6: e18987.
18. Pepe PE, Aufderheide TP. EBM vs. EBM: combining evidence-based and experienced based medicine in resuscitation research. Current Opin Crit Care, 2017; 23: 199–203.
19. Myers SP, Kutcher ME, Rosengart MR, et al. Tranexamic acid administration is associated with an increased risk of post-traumatic venous thromboembolism. J Trauma Acute Care Surg, 2019 Jan; 86: 20–7.
20. Lecker I, Wang DS, Whissell PD, et al. Tranexamic acid–associated seizures: causes and treatment. Ann Neurol, 2016 Jan; 79: 18–26.
21. Kirksey MA, Wilson LA, Fiasconaro M, et al. Tranexamic acid administration during total joint arthroplasty surgery is not associated with an increased risk of perioperative seizures: a national database analysis. Reg Anesth Pain Med, 2020 Jul; 45: 505–8.
22. Estreicher ME, Hranjec T, Pepe PE, et al. Spotting the clotting: hypercoagulopathy in COVID-19. EMS World, 2020 Aug; 49(8): 44–7.
23. Moore EE, Moore HB, Gonzalez E, et al. Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient. Transfusion, 2016 Apr; 56(Suppl 2): S110–S114.
24. CRASH-3 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet, 2019 Nov 9; 394: 23–32.
Paul E. Pepe, MD, MPH, FAEMS, MCCM, is coordinator of the Metropolitan EMS Medical Directors (aka “Eagles”) Global Alliance and medical director for special operations and tactical medicine for the the Broward County (Fla.) Sheriff’s Office.
Jonathan Jui, MD, MPH, FACEP, FAEMS, is a Resuscitation Outcomes Consortium (ROC) co-investigator and longstanding EMS medical director for the city of Portland and Multnomah County, Ore., as well as the Oregon State Police.
James P. Roach, DO, FACEP, is chair of the Cleveland Clinic Florida Emergency Department and chief medical officer for the Broward Sheriff’s Office in Broward County, Fla.
John B. Holcomb, MD, FACS, a retired colonel from the U.S. Army, is a general surgeon and senior scientist at the University of Alabama Center for Injury Science and was previously commander of the U.S. Army Institute of Surgical Research, as well as a 19-year member of the U.S. DOD Joint Trauma System Committee on Tactical Combat Casualty Care.
