THE USE OF TRANEXAMIC ACID IN
TRAUMA PATIENTS IN A PREHOSPITAL
AND HOSPITAL SETTING.
A SYSTEMATIC REVIEW
LTHUANIAN UNIVERSITY OF HEALTH SCIENCES
Department of Disaster Medicine
TABLE OF CONTENTS
Summary ... 3
Summary in Lithuanian ... 4
Acknowledgement ... 5
Conflict of Intrests ... 6
Abbreviations ... 7
Terms ... 8
Introduction ... 9
Aims and Objectives ... 10
Methods ... 11
Results ... 12
Mechanism of Action of Tranexamic acid ... 12
Coagulopathy in Trauma ... 13
Tranexamic acid in Trauma ... 15
Indications and Contraindications ... 15
Outcomes ... 17
Adverse Reactions ... 20
Current Management of Traumatic Bleeding ... 21
SUMMARY
Author’s name: Lewar HawezTitle of thesis: The use of Tranexamic Acid in trauma patients in a prehospital and
hospital setting. A systematic review.
Abstract of the thesis: Tranexamic acid (TXA) is an antifibrinolytic agent which have
been found to decrease haemorrhage and mortality, caused by said haemorrhage, following a traumatic injury. This area of research is relatively new and therefore offers limited studies. However something all studies have in common is the concern regarding the risks of thromboembolic events with contradictory results published between
different studies. Some offer results with statistical insignificance between a TXA and control group while others infer that TXA is not beneficial for all patients but may create more harm for their survival. Current evidence stands that the sooner TXA is
administered the better, for best possible results to be given within 1 hour but the
window for administration for a benefit stretches up to 3 hours, beyond 3 hours evidence states that it actually increases mortality instead of decreasing it. There are also some interesting results indicating that TXA benefits the trauma population with a higher injury burden, characterized by ISS >15 and GCS <8, and those in a low- and middle income countries that have limited resources along with a less developed trauma system.
Aim: To evaluate the administration of TXA and its effect on ED patients that has been
traumatically injured in a pre-hospital setting.
Objectives
1. To determine the benefits of TXA being administered in a prehospital/hospital setting 2. To compare mortality based on time of administration of TXA
3. To determine prognosis of TXA administration in a prehospital/hospital setting
Method: A literature search was conducted to find, exclude and collect articles relative to
the topic of TXA, its MOA, usage in trauma, adverse reactions and others.
A general search was performed in 10/2018 in large databases and trauma/emergency journals; PUBMED/NCBI, ScienceDirect, Wiley Online Library, BMJ, EBSCO
Conclusion: TXA shows better survival benefits the earlier it is administered in patients
SUMMARY IN LITHUANIAN
Darbo anotacija: Traneksamo rūgštis (TXA) yra antifibrinolitinis preparatas, kuris pagal
tyrimų duomenis sumažina kraujavimą ir potrauminį mirtingumą dėl minėto kraujavimo. Ši tyrimų sritis, palyginti, nauja, todėl jos tyrimų yra nedaug, bendras visų tyrimų bruožas yra nerimas dėl tromboembolinių komplikacijų rizikos, tačiau rezultatai, lyginant
skirtingus tyrimus, yra prieštaringi. Dabartiniai tyrimai rodo, kad kuo anksčiau taikoma TXA, tuo geriau, siekiant geriausių įmanomų rezultatų, reikėtų ją duoti 1 valandos laikotarpyje po patirtos traumos, tačiau palankus vaistų davimo laiko intervalas yra iki 3 valandų, vėliau, kaip teigia faktai, tai faktiškai padidina mirtingumą vietoj to, kad jį sumažintų. Taip pat yra rezultatų, rodančių, kad TXA padeda sunkesnę traumą patyrusiems pacientams (ISS >15 ir GCS <8), ir tiems, kurie gyvena šalyse, kurių
gyventojų pajamos mažos arba vidutinės ir dėl ribotų išteklių traumos sistema yra mažiau išvystyta.
Tikslas: Įvertinti traneksaminės rūgšties naudojimą traumas patyrusiems pacientams,
prehospitalinei pagalbai, lyginant su stacionaro sąlygomis.
Uždaviniai:
1. Nustatyti TXA, skiriamos prehospitalinei pagalbai ir stacionaro sąlygomis, naudą. 2. Palyginti mirštamumą, remiantis TXA davimo laiku.
3. Nustatyti TXA skyrimo prehospitalinei pagalbai ir stacionaro sąlygomis prognozę.
Metodas: Buvo atlikta literatūros paieška, siekiant surasti, atmesti ir surinkti straipsnius,
susijusius su TXA tema, jos skyrimo būdu, naudojimu traumų atveju, šalutinius poveikius ir kt.
2018 metų spalio mėnesį buvo atlikta bendra paieška didelėse duomenų bazėse ir žurnaluose, rašančiuose traumų ir skubios medicinos pagalbos temomis;
PUBMED/NCBI, ScienceDirect, Wiley Online Library, BMJ, EBESCO
Išvada: Kuo anksčiau TXA duodama pacientui, patyrusiam sunkią traumą, tuo didesnė jo
išgyvenimo tikimybė, nesant jokių svarbesnių šalutinių poveikių, tačiau ji
ACKNOWLEDGMENT
CONFLICT OF INTEREST
ABBREVIATION
TXA – Tranexamic acid
WHO – World Health Organization MOA – Mechanism of Action tPA – Tissue Plasminogen Activator
PAL-1 – Plasminogen Activator Inhibitor-1 TAFI – Thrombin-activable Fibrinolysis Inhibitor EACA – Epsilon Aminocaproic Acid
ED – Emergency Department APC – Activated Protien C DCR – Damage control surgery MTP – Massive Transfusion Protocol ISS – Injury Severity Score
FFP – Fresh Frozen Plasma PRBC – Packed Red Blood Cells PLAT – Platelets
MODS – Multiorgan failure TEG – Thromboelastometry
aPTT – Activated Partial Thrombin Time PT – Prothrombin Time
TERMS
Prehospital – Treatment occurring at places before arriving to the hospital such as site of trauma and on the way to the hospital
Thromboembolic event – Process of a clot formation in the blood vessels that might lead to plugging of a vessel at a distal organ/extremity
Thrombin-switch – After a severe traumatic injury the thrombin forms a complex with endothelial protein C receptors causing the thrombin to initiate anticoagulation instead of coagulation.
Hyperfibrinolysis – Increase of fibrinolysis following the increase of activated C protein causing coagulopathy
Acute traumatic coagulopathy – Endogenous coagulopathy induced early after trauma, associated with increased organ failure and mortality
Trauma-induced coagulopathy – Preceded by acute traumatic coagulopathy, a multifactorial trauma-associated coagulopathy
Massive transfusion protocol – a transfusion of ≥10 units of packed red blood cells within 24 hours of injury
Permissive hypotension – Short term allowance of hypotension for the benefit of the trauma patient by restricting fluid infusions
Damage control surgery – Surgery technique for trauma patients exploring and offering immediate short-term/final treatment of potential life-threatening injuries
INTRODUCTION
According to WHO in 2016 road injuries was the eight leading cause of death as can be seen in figure 1 [1]. It is the main cause of death in the paediatric and young adult population (5-25 years) and claims approximately 1.35 million lives each year,
accounting for 9% of the global mortality [2,3]. Death after trauma can be divided into three categories (1) immediate, death that occurs at the scene or within 1 hour of arrival to trauma centre, (2) early, death that occurs within 24 hours and (3) late, death that occurs after 24 hours. One of the main contributing factors of the high mortality rate in trauma has been proven to be traumatic bleeding alongside CNS injury, exsanguination being more relevant in the first two categories and decreases over time after injury [4-6]. Grassin-Delyle et al. infers that approximately one third of mortality associated with trauma is the result of preventable haemorrhage [21].
Figure 1. Data from WHO showing the top ten global causes of death [1]
There has been previous research into finding ways to reduce mortality caused by trauma and specifically bleeding. One of the more interesting and plausible
alternatives, due to its efficacy and cost-effectiveness [36,40] is the lysine analogue TXA. The interest in TXA is relatively recent and it reached its status as a popular alternative after the large scale, multinational CRASH-2 study in 2010 [8]. The usual on-label use of TXA includes severe menorrhagia and prophylaxis in case of a tooth extraction in
AIMS AND OBJECTIVES
The aim of this literature review is to evaluate the administration of TXA and its effect on ED patients that have been traumatically injured in a pre-hospital setting.
Objectives:
1. To determine the benefits of TXA being administered in a prehospital/hospital setting
2. To compare mortality based on time of administration of TXA
METHODS
A literature search was conducted to find, exclude and collect articles relative to the topic of TXA, its MOA, usage in trauma, adverse reactions and others.
Initially a general search was performed in 10/2018 in large databases and trauma/emergency journals; PUBMED/NCBI, ScienceDirect, Wiley Online Library,
BMJ, EBSCO
Keywords: “trauma”, “accidents”, “tranexamic acid”, “TXA”, “prehospital”, “hospital”, “emergency department”, “treatment”, “adverse reaction”, “benefit”, “mortality”,
“criteria”, “monitoring”. While this work focuses on the usage of TXA in trauma related patients suffering from haemorrhage and road injuries, relative to the keywords above, studies which include the keywords “Traumatic brain injury”, “brain surgery”, “cardiac surgery” are also included in this review in order to compare certain factors.
RESULTS
MECHANISM OF ACTION OF TRANEXAMIC ACID
One of the main concepts in this article is the fibrinolytic system, its activation and ways to counteract the system in order to reduce the mortality rate in cases when the process will prove to be fatal. As to say in cases where extensive bleeding is a risk or actively occurring, for this article meaning bleeding trauma cases.
The fibrinolytic process is a normal physiological process which causes the degradation of clots formed by fibrin. It starts by increasing the affinity of the
plasminogen activators, tPA and urokinase, for plasminogen to convert it to its active form plasmin. Plasminogen itself does not do much as it is inactive, its active counterpart on the other hand plasmin breaks down fibrin and activates monocytes, neutrophils and the complement system, promoting an inflammatory response [20,22,41-45]. In a healthy person this process is well regulated by a balance between its activators and inhibitors (Table 1) through a feedback process [20,41]. In a bleeding trauma case however the balance is disrupted, shifted and causes an increase in the plasmin activation leading to increased bleeding as well as an increase in the pro-inflammatory process, Monocyte- released cytokines, and eventual multi-organ failure along with other coagulation disturbances which will be discussed later [20].
Activators Inhibitors Endothelial activation (Injury, stretching, occlusion) TXA
Contact activation PAI-1 Stress/physical activity TAFI
tPA EACA
Urokinase Alpha2-antiplasmin
Table 1. Fibrinolysis activators and inhibitors
these concentrations are avoided due to the increased risk of adverse reactions and sensitivity [21,22,33].
At a concentration as low as 16 µg.ml-1 TXA is shown to inhibit the platelet activation by plasmin meaning that a low concentration is sufficient enough to inhibit the majority of tPA-induced fibrinolysis. For higher concentrations, >150 µg.ml-1, it might further inhibit urokinase-induced fibrinolysis and the plasmin-induced pro-inflammatory effects but carries higher risks.
Fig.2. Effect of TXA on fibrinolysis following tissue injury [20]
COAGULOPATHY IN TRAUMA
Coagulopathy in trauma is one of the larger contributors to an early but preventable death in large due to the multifactorial aetiology and its reversible anticoagulation. Discussing TXA in relation to acute traumatic coagulopathy/trauma induced coagulopathy begins at the time of trauma. The injury causes haemorrhage, leading to shock, acidosis and hypothermia which are contributing triggers of ATC. One of the main drivers in the development of ATC/TIC in trauma remains protein C
activation, the traumatic injury in combination with hypoperfusion leads to the release of
Several studies have documented a trend of the occurrence of acute traumatic coagulopathy (ATC) within the first hour of traumatic injury, approximately 25% of trauma patients that arrive to the ED show laboratory signs of ATC. The incidence of traumatic coagulopathies are also linked to an increase of (1) transfusion requirements, (2) ICU and hospital stays, (3) MODS, (4) infection and a worsening of prognosis regarding both morbidity and mortality after the onset of traumatic coagulopathies [7,15, 41-47].
Fig. 3. The lethal triad in trauma, strongly associated with poor prognosis and outcomes and
must therefore be prevented before the onset. [17]
The poor prognosis is caused by the combination of the established coagulopathy with acidosis and hypothermia (lethal triad), fig.3, as it begins overloading the body and its functions. Previously the ATC was believed to be iatrogenic following massive crystalloid infusions and haemodilution, it was later proven that ACT was a trauma- induced endogenous coagulopathic event and would occur post-trauma regardless of infusion [17]. Of course the main goal is to avoid coagulopathies as a whole for patients with injuries but then again based on the statistics, 25% arrive to the ED with ATC, and action must be taken to avoid the progression of ATC to TIC.
USE OF TRANEXAMIC ACID IN TRAUMA
Indication and Contraindications
TXA a prehospital option in trauma is a relatively new area of use. It rose to interest after the first large scale study, and to this date the largest randomized study, CRASH-2 in 2010 [8-10]. Since its publishing the studies following have based the dose and its inclusion criteria on it with some adjustments. In table 2 the inclusion criteria of the five largest, two of them ongoing, studies is seen.
Study Evaluation of TXA need
Critera
CRASH-2 [10] Clinical Trauma injury >18 years of age SBP <90, HR >110
Ongoing haemorrhage or risk of haemorrhage,
Within 8 hours of trauma MATTERs [25] Clinical + ROTEM Trauma injury
>18 years of age
Significant haemorrhage requiring transfusion,
Evidence of hyperfibrinlysis on ROTEM CAL-PAT [65] Clinical Trauma injury
>18 years of age SBP <90, HR >120 Injury within 3 hours >500 ml blood loss
Bleeding not controlled by direct pressure or tourniquet
Major amputation of any extremity PATCH (ongoing)
[67-68]
Clinical Trauma injury >18 years of age Injury within 3 hours COAST >3,
STAAMP (ongoing) [15]
Clinical Trauma injury >18 years of age Injury within 3 hours SBP <90, HR >110
Air medical transport within 2 hours of injury
Table 2. Inclusion criteria of TXA administration studies
administrating TXA at the site of trauma (prehospital) within 8 hours of injury they noticed a trend of increased all-cause mortality, as well as an increase of thromboembolic incidence, if TXA was administered after 3 hours. The recommendations were therefore changed from 8 hours to within 3 hours as they the trial found that the all-cause mortality was significantly decreased with “[…] no apparent increase in fatal or non-fatal vascular occlusive events” [8].
For the use of TXA in an emergency setting contraindications has not been established in the classical sense, there have been exclusion criteria for each study that are quite similar
1. Pregnancy, 2. Age <18/>90,
3. Inability for IV access, 4. Spinal cord injuries,
5. Cardiac arrest >5 min 6. Penetrating cranial injuries 7. Exposed brain matter 8. Hanging/drowning victims These exclusion criteria’s are fairly basic and have been adjusted to the level of risk, the logistic difficulties regarding the administration and relevance to TXA
administration and the aim of each individual study. After the CRASH-2 study all have chosen to exclude patients who have sustained traumatic injuries older than 3 hours. Thanks to the CRASH study and its results, along with all the subsequent reviews and studies following it, the dangers regarding administration after three hours is well known.
Contraindications for other uses, both on- and off-label, on the other hand have been established [37, 41].
1. Relative contraindications a. Renal dysfunction
b. Uncontrolled seizure, c. Previous VTE,
d. Colour vision impairment e. Pre-existing coagulopathy,
f. Oral anticoagulant treatment, g. Oral contraceptives,
h. Urinary tract bleeding due to ureteral clotting,
2. Absolute contraindications a. Active intravascular clotting,
c. Concomitant with Active prothrombin complex concentrate or factor IX complex (increase thromboembolic risk)
The problem in TXA administration in pre-hospital lies with the impossibility of assessing these contraindications at the site of injury. An unconscious victim or a victim in shock would be unable to answer questions regarding their medical history along with no laboratories to help establish diseases that are contraindicated out in the field. If however TXA administration is delayed until the patient has arrived to the hospital some of the information would be more accessible to the staff and a more informed decision would be made, presuming that it all occurs within the 3 hour window. Regarding the relative contraindications it seems that the benefit of TXA outweighs the potential future harm as the haemorrhage is far more life-threatening than the manageable issues that might arise in the future
Outcomes
As stated before the CRASH-2 study is the first and remains the largest civilian study to date, it involved 274 hospitals in 40 countries and divided the patient pool I nto two cohorts, a TXA cohort and a placebo controlled cohort. The administration of TXA was based on clinical signs, table 2, at risk of or showing significant haemorrhage following a trauma after which a bolus dose of 1g/10min was given followed by a
continuous infusion of 1g/8h. The results showed a reduction of the all-cause mortality is given within 3 hours, if given within 1 hour mortality was reduced by one third, without any significant difference in transfusion requirement or any thromboembolic/vascular events between the two cohorts. An issue with the study remains the low precision of both transfusion requirements in addition to reports regarding ADRs such as PE/DVT, MI, stroke and multi-organ failure the authors however, defends the choice as these effects might be expected due to the nature of the antifibrinolytic agent.
As can be seen in the criteria table the original time frame for TXA
administration after a trauma was eight hours but was altered to three hours instead due to the opposite effect TXA had on the patient. Gayet-Ageron et al [26] collected the
evidence from the CRASH-2 along another large scale trial called WOMAN [66], which evaluates TXA in postpartum haemorrhage, and examined the effect a delay of TXA treatment have on the effectiveness of the antifibrinolytic. A 10% decrease in
effectiveness every 15 min the administration is delayed was determined. In fig. 5 the decline of a positive effect of TXA is shown, by hour three it can be seen that TXA no longer has any positive effect (white square), for the lower confidence interval it occurs as early as 135 minutes. This reinforces the conclusion that TXA should be administered as early as possible and therefore recommends a prehospital administration if not the risk of death caused by exsanguination increases due to the use of TXA.
Fig.4.Association between TXA delay and positive effect [26]
After a systematic review of CRASH-2 in 2012 it was shown that the annual death rate of avoidable death was approximately 400,000 due to traumatic bleeding if however TXA was given within 1 hour 128,000 could be prevented and within 3 hours 124,000 [24].
The MATTERs study is a military study placed in Afghanistan which showed slightly different results comparing to CRASH-2. There were four cohorts in two groups, (1) Patients who overall received TXA v. No TXA cohort and (2) Patients who required massive transfusions (MT) who received TXA v. MT no TXA.
compared to their no TXA counterparts with a larger statistical difference in the MT cohorts with the higher injury burden and higher transfusion rates. This shows that TXA benefits patients with an ISS > 15 i.e. a higher injury burden, the conclusion is further reinforced when it becomes clear that the ISS of the overall cohort is generally higher in the TXA > no TXA in combination with the absolute reduction in mortality. While the ISS in the MT cohorts are similar the MT.TXA group has a greater number of patients with a depressed GCS score and severe extremity injury.
Regarding the transfusion requirement it remained the same in the two MT cohort with ≥10 units, between the overall TXA v. No TXA groups it was shown that the TXA group required more transfusions.
The incidence of thromboembolic events were recorded to be higher in the TXA groups of both cohorts however since the patients in the study had a high injury burden which is typically associated with these types of events. It is worth nothing that the occurrence of DVT/PTE provided no casualties and the actual mortality risk reduction was as high as 49% in the MT.TXA cohort.
The third finished study, albeit the smallest of the selection, is the CAL-PAT study which includes 8 centres in California. The inclusion criteria is clinically based and the first dose, 1g/10 min, is given in a pre-hospital setting (on site, en route to hospital) while the second dose is given in-hospital although it is not a requirement instead it is on the ER doctors discretion. The results corroborated the results of both previous studies regarding the benefit on survival at 24 and 48 h as well as a reduction in the 28 day mortality, similarly to the MATTER study the reduction of mortality seemed to be the most significant in the MT.TXA cohort typically consisting out of a pool with higher ISS and lower GCS. Contrary to the MATTER study on the other hand is the decrease of blood product transfusions.
All three studies have noticed and noted a higher benefit for trauma patients with a higher injury burden. For CRASH-2 a trend of a higher benefit for patients with a SBP <75 mmHg compared to the control cohort than any other TXA subgroup was noticed along a longer length of stay (LOS) for the TXA cohort on the other hand this can be attributed to the higher injury burden of the TXA cohort. As for the other two it is clear thanks to the MT cohorts and the significant absolute mortality reduction.
Some studies infer that TXA is not beneficial for all patients, results show that patients with hyperfibrinolysis had no benefit on survival and that TXA in the presence of physiological fibrinolysis actually increased mortality [12, 34, 35]. The main difference from the studies with favourable outcome are two things (1) the place of administration being in-hospital in contrast to a pre-hospital administration and its subsequent (2) delay in administration.
Adverse Reactions
Generally speaking TXA affects all systems in the body with more of a documentation of the ADR regarding long-term use and elective surgeries. The most obvious would be in cases of allergies where there might be dermatological
manifestations or something more severe such as anaphylaxis there has been however no mention of such attacks in trauma. For long term uses headaches, nausea, abdominal pains and diarrhoea are the most common reactions but the most dangerous are thromboembolic event and its possible consequences cerebral infarction and cerebral ischemia [37, 60]. Increased risk of thromboembolic events are associated with the use of oral contraceptives; central retinal artery occlusion, retinal vein occlusion, DVT, PE etc.
CURRENT MANAGEMENT OF TRAUMATIC BLEEDING
In developed countries where advanced trauma care is available adequate physical haemorrhage control in combination with damage control resuscitation is the foundation for bleeding trauma patients.
DCR is a multimodal strategy that consists out of three components (1)
permissive hypotension, (2) haemostatic resuscitation and (3) damage control surgery, see
fig. 5 [17, 18, 27]. The aim of this combination strategy is to make sure the patient
receives early and potentially life-saving treatment, primarily by aggressively treat and in cases to avoid the lethal triad (fig. 3).
Figure 5. Components of damage control resuscitation [17]
DCR is initiated as soon as possible at the site of trauma by restricting the amount of crystalloid fluid. Previously, in order to avoid a state of shock, large volume crystalloid infusion was implemented, however even as the main focus of trauma care remains more or less the same with trying to avoid a state of shock, there is a general consensus to avoid large volume infusion of crystalloids. Evidence states that it may interfere with the physiological haemostatic mechanism and may actually exacerbate bleeding as well as allowing iatrogenic coagulopathy [17, 41-44]. The restriction of free volume infusion comes with its own limitations as this allows for a short–term state of hypotension.
Cannon et al. recommends TXA to be used only as an adjunct treatment and only in-hospital within 3 hours of trauma, with close monitoring for VTE, as they find a lack of clear benefit to administer it in a prehospital-setting in combination with the already established DCR [18]. The authors argue that there have not been enough studies
regarding the efficacy of TXA as a priority treatment and feel that the MT/DCR-protocol should not be delayed nor neglected in favour for TXA. It is acknowledged that while there is not enough evidence for TXA as a first choice it is a safe drug with seemingly life-saving properties and should therefore be given as a haemostatic adjunct. While some studies have stated that this is true they also believe that in countries with less developed trauma care systems TXA would benefit the survival rate as they lack resources to properly implement a DCR protocol [17, 27].
Other studies in countries with proper DCR-P in place believe in the implementation of TXA as a priority routine, the sooner the better, to be administered pre-hospital as previously stated [28-30]. Administering TXA by qualified personnel along with the implemented protocols for major trauma showed favourable results.
RECOMMENDATIONS
Administration
Alburaih [36] conducted a survey among trauma surgeons and emergency physicians at trauma centres of various levels in the US where approximately half either did not know or were unsure if TXA was a part of their MTP at the institutions. 75% responded that they were comfortable using TXA based on the current evidence if they knew they had access to it. This indicates that one of the major barriers regarding the limited use of TXA is the lack of knowledge that they have access to it. On the other hand it must be noted that other barriers also includes having no knowledge about the time limitations of TXA administration and doubt regarding the CRASH-2 results.
care.
This can help optimize the administration quantity, avoid double or missed doses as well as confusion surrounding patient selection. It can be argued that due to “sooner the better” limitation of TXA alongside a proper and agreed upon protocol all of these issues can be avoided regardless of who decides on the administration of TXA. At the same time the fact that the current trauma protocols does not rely on TXA and having more than one responsible for the decision of administration might hinder the
resuscitation results and cause more confusion than anything.
The main issue of allowing the responsibility to solely depend on the surgeon/emergency physician is the time constriction. As can be seen in fig. 4. TXA administration delay is strongly associated with a decrease in a positive effect and loses it completely after three hours, But the responsibility should depend on several factors (1) the centre and its treatment possibilities (2) the distance between the location of trauma and the trauma centre/ED, (3) the incorporation of TXA in the in-hospital MTP and (4) the paramedic response time.
Studies conducted by Valle E. et al. [34] and Harvin J. et al. [35], in Miami and Houston respectively, were based patients receiving in-hospital administration of TXA at the discretion of the surgeons. Both showed an increase in mortality in the TXA cohort.
In the Miami study TXA was administered if the patient was in need of
transfusion or emergency surgery meaning that the cohort received TXA in-hospital, after a transfusion and often perioperative. The authors mention a possible explanation of TXA exacerbating the hypotension already present and the progressed hypotension along with the haemorrhage is the cause of death.
patients received TXA as soon as possible, within 8 hours, before a transfusion with an increase in survival. During the MATTERs trial patient selection was based on the transfusion requirement or hyperfibrinolysis and within 1 hour, meaning the antifibrinolytic treatment was started before the transfusion and led to an absolute reduction in 24h mortality in the TXA cohort.
It can be assumed that implementing a TXA based protocol for trauma should include administration as soon as possible pre-hospital, be started before any transfusions and have clear guidelines of patient selections however more studies regarding the benefits for the implementation of TXA in a mature trauma system and DCR-protocol needs to be investigated.
Dosage
The CRASH study set a precedent for the dosing of pre-hospital TXA administration in trauma of a loading dose of 1 gram over 10 minutes followed by a continuous infusion of 1 gram over 8 hours. This dosage has been followed by a series of different studies since its conception with favourable results using the same regiment such as Cole et al. [32] and Swendsen et al. [59] to name a few.
Regarding the pharmacokinetics a small study performed by Grassin –Delyle et al. showed that age, sex creatinine clearance, blood loss and volume of fluids
administered had no influence on the pharmacokinetics of TXA [21]. This study
consisting of 73 patients, involved in severe trauma, was performed in Switzerland, they received 1 gram of TXA, pre-hospital, at a median time of 43 minutes post-trauma. Blood samples were drawn on admission to the ED to be analysed for TXA concentration with the aim of developing a regiment which would allow the concentration to be maintained within a therapeutic concentration during the life-saving treatment of the patient within the hospital. The lowest target concentration was found to be 20 µg.ml-1 which could easily be maintained with the proposed loading dose of 1g pre-hospital for around 90 minutes. The authors argue that maintaining the higher limit of therapeutic concentration might be problematic with the current recommendation of 1 g bolus for 10 min followed by an 8 hour infusion as it seems to keep between 20-40 µg.ml-1 while higher
The study offers two recommendations both with a bolus dose given pre-hospital (1) “[…] one size fits all regimen” with the already proposed 1 g bolus followed by a continuous infusion after 90 min aiming at a lower therapeutic concentration or (2) a bodyweight-adjusted regimen with a bolus followed immediately by a continuous infusion aiming for a higher therapeutic concentration level that would range between 27.9 mg/kg – 22.1 mg/kg.
Studies surrounding the safety of concentrations reaching 150 µg.ml-1 have been done and showed no noteworthy impact on drug safety [57, 58]
Monitoring
Due to the risk of a thromboembolic event for any type of use of any
antifibrinolytic a proper monitoring protocol should be in place regardless if the risk is insignificant, significant or anything in-between. Starting from CRASH-2 the monitoring entailed routine blood tests but no specific laboratory parameters in regards to
coagulation and TXA concentration, later studies contest this explaining that this is insufficient and developed the monitoring recommendation. While it is true that plasma- based testing (aPTT, PT and INR) have traditionally been used for monitoring of patients receiving anti-coagulant treatment the question concerning whether or not it is enough remains. Other parameters such as D-dimer and inflammatory markers is available may also help measuring the effectiveness of TXA [12, 68]
Studies focusing on viscoelastic monitoring (TEG, ROTEM) seem to have a favourable outcomes, not only do they accurately identify fibrinolysis but also deduces the phenotypes [12, 41]. Whether or not to do the testing and then administer is under discussion as it will delay and decrease the efficacy of TXA as stated by Gayet-Ageron et al [26], it does provide to be a valuable tool in monitoring the state of fibrinolysis of the patient and might help deciding further treatment/action. Some centres are able to offer their EMS access to ROTEM at the scene of injury which might show clot-stabilization and a decrease of fibrinolytic activity, reinforcing “the-earlier-the-better” mentality that surrounds TXA in trauma [14]
Conclusion
The main benefit of TXA in prehospital-setting remains the time sensitive nature of TXA administration while a hospital setting have resources readily available such as blood-products and operating rooms. The early administration ensures improved early survival with its maximum effect if given within 1 hour, however if administered after 3 hours shows to increase mortality due to bleeding. There were no recorded deaths or long-term morbidities caused by the ADRs of TXA and shown to have the best prognosis of survival in patients with higher injury burdens (ISS>15, GCS <8).
Based on the evidence TXA is shown to help early survival and should be implemented in routine trauma care in haemorrhaging cases and to be given at the site of injury (prehospital) for early administration before transfusions. However further
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