Is it time for TXA in the prehospital care setting? Howie Mell our prehospital care expert says yes.
TXA in Pre-Hospital Care
Howard Mell MD
International Trauma Life Support (ITLS) recently came out with a position statement on the use of tranexamic acid (TXA) in the management of traumatic hemorrhage in the field. They concluded that, “ITLS believes that there is sufficient evidence to support the use of TXA in the management of traumatic hemorrhage in the adult patient, pursuant to system medical control approval. Following initial resuscitation including control of external bleeding and stabilization of airway, consideration should be given to administration of TXA during early stages of transport.” (https://www.itrauma.org/ wp-content/uploads/2014/05/TXA-Resource-Document- FINAL.pdf)
The use of TXA in the prehospital setting is an emerging trend in the United States. Mell is the medical director for the Fire Department in Newark, Ohio, which is the first department to place TXA on their ground ambulances. They have accumulated a year and half of experience, and the initial impression is that it helps to control hemorrhage in severely injured patients. Average transport time to their receiving hospital is around 45 minutes.
There have been three major studies.
CRASH-2 trial collaborators, et al. 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 3;376(9734):23-32. PMID: 20554319.
There are multiple papers stemming from this study. It was a randomized, placebo-controlled, double blinded study with over 20,000 patients. It was carried out in Western Europe, sub-Saharan Africa and western India, which has led to some questions regarding its generalizability. Some critics point out that there were no defined inclusion criteria. The gestalt of the treating physician led to enrollment in the study. If the physician felt that the patient had a significant trauma, the patient was enrolled.
While the two study arms were randomized appropriately and looked similar statistically, would the same care be given in the United States?
Some research looking at subgroups indicates that the drug is most effective if it is given within one hour of injury. If the drug is given more than 3 hours after injury, it may lead to harm.
Realistically, if you are involved in a serious injury in most of the United States, you won’t have reached the trauma center and will be under the care of EMS or an outlying hospital that will arrange transfer to a trauma center. Some of the centers in developing nations are similar to the EMS setting, with minimal diagnostic equipment.
The study showed a 1.5% reduction in all-cause mortality at 28 days without significant adverse effects.
The number needed to treat was 67. The cost to administer a single dose is $107. The cost to save a life is about $7000.
The dosing scheme was 1 gram over 10 minutes, followed by a second gram over eight hours.
Morrison, JJ et al. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012 Feb;147(2):113-9. PMID: 22006852.
This was an observational trial but suggested that the number needed to treat fell significantly in more severely injured patients. The group receiving TXA was more severely injured but had improved mortality rates. In the most severely injured patients, the number needed to treat fell as low as 7.
Morrison, JJ et al. Associations of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg. 2013 Mar;148(3):218-25. PMID: 23670117.
This was a randomized, placebo-controlled trial that looked at cryoprecipitate, tranexamic acid, both, or placebo. The best outcomes were with cryoprecipitate and tranexamic acid. However, tranexamic acid alone was independently associated with markedly decreased mortality.
The CRASH3 trial is in protocol phase with an anticipated publication date of 2018.
The PATCH trial is happening in Australia and looks at the prehospital administration of tranexamic acid for control of hemorrhage.
How does tranexamic acid work? When we have an injury, we make a fibrin clot right away. However, as soon as we make the fibrin clot, we begin to make the factors to break it down. We release tPA, which binds with plasminogen to make plasmin, which breaks down fibrin clot. This presents two problems in trauma: 1) the clot is gone, allowing bleeding; and 2)if enough clots are broken down after massive trauma, theresulting products can lead to a coagulopathy that can worsen bleeding. The ideal drug is one that stabilizes the fibrin clot.
TXA binds to a lysine-binding site on the plasminogen so that the plasmin created upon binding with tPA is inactive. Thiskeeps the initial clot in place. It doesn’t cause a DVT or PE.It isn’t thrombogenic; it just stabilizes the fibrin clot.
The data shows it is most effective if it is given within the first hour after injury, placing it in the realm of EMS and outlying hospitals. The data shows that if the drug is given more than 3 hours after injury, it is not effective and can cause harm. It is also more effective when it is coupled with a blood component-based resuscitation effort. It has been included in a lot of massive blood transfusion protocols.
EMS medical directors may consider using tranexamic acid in the prehospital setting in patients with significant trauma and an anticipated time of over an hour before hospital evaluation. It may be worth adding it to the formulary in outlying hospitals and Level 3 trauma centers, who anticipate transport of patients for higher level of care, so that patients may receive TXA in a timely manner.
Dosing. If you are administering a drug over ten minutes, do you need pumps? The Newark Fire Department assembled kits, which contain tranexamic acid (which comes in 1 gram per 10mL of liquid), a 10mL syringe, a filter needle, an injection needle, a 50 cc bag of normal saline and some 10cc/mL drip tubing, and a bracelet that says “TXA given.” To give the drug over ten minutes, draw up the drug into the 10mL syringe and inject into the 50mL bag of normal saline. This gives you a bag containing 1 gram of tranexamic acid in 60mL of fluid. Hang the 10cc/mL tubing attached to the bag. Set the drip at 1 drip per second. There are 600 drips in 10 minutes. There is no need for a pump and you will administer it within close to ten minutes.
This is not to say that tranexamic acid is more effective than the tools available to trauma surgeons at major trauma centers. It is better than what is currently available when 45 minutes away from the nearest trauma center or in a free-standing ER with a walk-in trauma experiencing significant hemorrhage. It is beneficial when there is proper patient selection. It shouldn’t be given to everyone or when there are better alternatives available; it should be given when there is no better option.