Haemorrhagic shock is a leading cause of death internationally, whether from serious trauma (Grassin-Delyle et al, 2018; Neeki et al, 2018) or other conditions such as postpartum haemorrhage (Shakur et al, 2010; Cannon, 2018). Severe haemorrhage can compromise the body's ability to form and maintain clots. This is because haemorrhage, hypoperfusion and haemorrhagic shock may result in dysregulation of coagulation systems, through pathologic release of fibrinolytic enzymes. These fibrinolytic enzymes have the effect of prematurely breaking down clots within the haemorrhaging patient, thereby compromising haemodynamic stability through excessive thrombolysis (Huebner et al, 2017; Grassin-Delyle et al, 2018; Neeki et al, 2018).
Tranexamic acid (TXA) inhibits the premature breakdown of blood clots, which may occur following severe haemorrhage. TXA is a synthetic derivative of lysine that inhibits the fibrinolysis of blood clots (Roberts, 2015; Jawa et al, 2016; MIMS, 2019). TXA appears to be a promising drug that—if administered early, such as during the prehospital phase of care—may reduce mortality from severe haemorrhage (Stansfield et al, 2020). In the United Kingdom (UK), TXA was first introduced to the South Western Ambulance Service Trust in December, 2011 (Paudyal et al, 2017) and has since become widely used by paramedics across the UK when treating patients with severe internal or external haemorrhage, postpartum haemorrhage and head injury (Association of Ambulance Chief Executives, 2019). However, other studies suggest that further research is required to demonstrate the efficacy of prehospital TXA administration (Napolitano, 2017), and it is perhaps for this reason that TXA is not yet widely used across all international ambulance services. For example, TXA administration across Australian ambulance services is largely restricted to the PATCH (2019) research study, while paramedic use of this drug in New Zealand has only recently commenced (St John New Zealand, 2019).
The purpose of this review is to explore current literature regarding prehospital TXA administration for patients suffering severe haemorrhage following trauma, and to discuss whether this drug should be more widely used across modern international ambulance services.
Methods
A literature search was undertaken in August, 2019, using EBSCO Host, ProQuest and PubMed databases. Two search strategies were adopted: the first sought to identify peer-reviewed articles relating to prehospital administration of TXA, while the second sought to capture peer-reviewed articles reporting on the effects of TXA on mortality rates in trauma (Table 1). It was felt that the second search strategy would help to inform this study of the magnitude of benefit that may be associated with TXA administration for severe trauma patients. Keywords were searched using the Boolean operators ‘AND’ to search multiple terms together, and ‘OR’ for related terms. Limits, such as date range and English language, were applied to further refine the results, where needed.
| Search strategy | Databases searched | Keywords searched | Limits applied* |
|---|---|---|---|
| 1. |
|
|
|
| 2 |
|
|
Species: Humans |
This search strategy resulted in more than 100 articles being identified for initial review. The titles and abstracts of these articles were then assessed, resulting in duplicates and superseded articles being removed. Articles that focused on surgical outcomes, obstetrics, paediatrics, or on the eligibility of patients to receive proposed dosage schemes were also excluded. At the conclusion of this process, eight articles were retained for review. Thereafter, sources including MIMS Online (2019), citations within the selected articles, and related papers were also accessed and reviewed to provide further context and to better inform this review.
Limitations of this methodology were that a wider range of journal databases (including Cochrane and Emcare) may have yielded additional results, as may have an extended date range. However, the search strategy (which reviewed and—where relevant—included citations drawn from the original articles) ensured that major studies on this topic were captured and appropriately integrated into this review.
Results
Six common topics were identified across the eight peer-reviewed articles selected for this review (Table 2). These topics related to prehospital TXA administration following trauma and:
| Main themes | Common topics identified in this study |
|---|---|
| Mortality |
|
| Traumatic brain injury |
|
| Adverse effects |
|
| Indications |
|
| Contraindications |
|
| Dose and administration route |
|
TXA appears to be effective at reducing the mortality of trauma patients when administrated within 3 hours following injury, without increasing the incidence of fatal adverse effects (Roberts, 2015; Wafaisade et al, 2016; Huebner et al, 2017; Roberts et al, 2017; Grassin-Delyle et al, 2018; Neeki et al, 2018). Studies by Roberts and colleagues (Roberts et al, 2014; Roberts, 2015) found that TXA can reduce the risk of mortality from bleeding by approximately 30% when given within 1 hour from time of injury. However, it is also noted that TXA administration more than 3 hours following an injury can be significantly deleterious for the patient (Roberts, 2015; Huebner et al, 2017; Roberts et al, 2017; Grassin-Delyle et al, 2018; Neeki et al, 2018).
Debate exists within the selected articles as to specific indications for TXA administration in trauma patients. Some would argue that TXA is only indicated in trauma patients with signs of haemorrhagic shock (Neeki et al, 2018), while others assert that TXA should be given as quickly as possible to all trauma patients whenever a life-threatening haemorrhage is suspected (Roberts, 2015; Huebner et al, 2017; Roberts et al, 2017), provided this occurs within 3 hours from time of injury. The reasoning for the latter argument is that traumatic haemorrhage leads to systemic hypoperfusion, which causes the release of tissue plasminogen activator from endothelial organelles, called Weibel Palade bodies, resulting in systemic fibrinolysis and worsening haemorrhage. Thus, early TXA administration can potentially avert this ‘coagulopathic bleeding’ by reducing the initial traumatic haemorrhage (Roberts, 2015).
Another concern evident within some of the reviewed articles is that studies conducted in military settings or within developing countries may not be immediately transferrable to modern international ambulance services, which deal with civilian populations and modern healthcare systems (Wafaisade et al, 2016). In recent years, attention has been given to smaller civilian studies; yet these studies have not yet been able to demonstrate the superiority of TXA use in modern civilian healthcare systems (Wafaisade et al, 2016; Napolitano, 2017).
Discussion
The benefits of TXA administration appear compelling. Previous high-quality studies that have been conducted in emergency, maternity and military settings—such as the CRASH-2 series (CRASH-2 Trial Collaborators, 2010; 2011), WOMAN (Shakur et al, 2010), and MATTERs (Morrison et al, 2012)—have pointed to an absolute risk reduction in 28-day all-cause mortality and reduction in death from haemorrhage (CRASH-2 Trial Collaborators, 2010; 2011; Shakur et al, 2010; Morrison et al, 2012; Fischer et al, 2016; Strosberg et al, 2016). However, a suggested limitation of some previous studies is that they have been conducted in regions with limited advanced trauma systems (Cornelius et al, 2019). Prehospital TXA administration must be examined within modern international paramedic practice settings (Queensland Ambulance Service, 2020).
The prehospital antifibrinolytics for traumatic coagulopathy associated with haemorrhage (PATCH) trial commenced in 2015 and aims to investigate the gaps of previous TXA trials, and includes ambulance service operations across Australia and New Zealand (PATCH, 2019; Queensland Ambulance Service, 2020). The PATCH trial is therefore likely to yield important information about the efficacy of prehospital TXA administration in modern civilian healthcare systems.
Other exciting studies such as CRASH-3 (CRASH-3 Trial Collaborators, 2019) have investigated the use of TXA in patients who have suffered traumatic brain injury. As it happens, the initial CRASH-3 results were reported in late 2019, shortly after completion of this literature review. While earlier civilian-based studies in modern healthcare systems have supported the use of TXA for those with severe traumatic injuries, the CRASH-3 study shows that patients with mild-to-moderate head injury are likely to benefit more from early TXA administration than those with severe head injury. This important study provides another dimension of understanding relating to the prehospital use of TXA across modern international health settings.
The use of TXA for uncontrolled postpartum haemorrhage is another important area of study that has received attention in recent decades (Shakur et al, 2018). Each of the aforementioned studies are likely to have implications for the prehospital use of TXA across modern international ambulance services.
Conclusions
It is evident that current literature generally supports prehospital administration of TXA for preventing exsanguination and haemorrhagic shock deaths. However, the widespread introduction of TXA within modern international ambulance services appears to be limited by unanswered questions, particularly in relation to the translation of TXA treatment protocols into civilian settings and the modern healthcare systems into which these ambulance services integrate. Studies currently underway (such as PATCH) offer the exciting potential to shed light on these questions and, potentially, precipitate the wider adoption of prehospital TXA treatment protocols. At this stage, however, it appears that further studies are required before prehospital TXA administration may be more widely adopted across modern international ambulance services.