1. Tranexamic Acid in Trauma Kids Too?
Developing EM 2014
Salvador da Bahia, Brazil
Suzanne Beno MD FRCPC
Trauma Co-Director
The Hospital for Sick Children
Toronto, Ontario

2. Objectives Review the evidence for tranexamic acid (TXA) in trauma
Identify current knowledge gaps for TXA in trauma
Discuss the use of TXA in pediatric trauma

3. Scenario 1
A young male presents to a trauma center extremely short of breath with stab wounds to his left flank. A chest tube is placed with return of a large volume of blood. He is stabilized but remains tachycardic, pale and agitated.

4. Scenario 2
A 5 year old girl on her bicycle is hit by a car. She presents with mild tenderness in her upper abdomen and tachycardia. Her FAST is grossly positive and an abdominal CT scan reveals a Grade 5 liver laceration. She is admitted to the ICU for observation.

5. Trauma Leading cause of death in North Americans 1-44 years of age
Hemorrhage most preventable cause of death after trauma in both adults and children
Hemostatic resuscitation and recognition of acute traumatic coagulopathy (ATC) and specifically hyperfibrinolysis
No medical therapy has proven survival benefit in children, but evidence DOES exist in adults

6. Tranexamic Acid Prevents the breakdown of existing clots
Mitigates the systemic anti-inflammatory response to massive hemorrhage
Tranexamic acid may have the potential to minimize trauma-induced coagulopathy by inhibiting fibrinolysis, thereby reducing blood loss and preventing death from acute hemorrhage. An alternative hypothesis is that TXA acts to mitigate the systemic anti-inflammatory response to massive hemorrhage.
TXA
Fibrin
Fibrinolysis

7. Tranexamic Acid
First clinical trial using oral TXA published in heavy menstrual bleeding - FDA 2009
Dental extractions with hemophilia reported in FDA approval 1986
TXA now widely used in many conditions
Extensive safety and efficacy profile in reducing the need for blood transfusions in elective surgery both adults and children
Postpartum hemorrhage
Gastrointestinal hemorrhage
Traumatic hyphema
Oral surgery
Pediatric urinary tract surgery
Hemophilia and VWD
dysfunctional uterine bleeding
spinal, craniofacial and cardiac surgery
liver transplantation
joint replacements
Cap AP et al. J Trauma 2011

8. TXA in Trauma What’s the evidence?

10. Randomized to TXA versus placebo
prospective randomized placebo-controlled trial of 20,211 patients, 274 hospitals, 40 countries
Inclusion criteria: adults (16 years and up) with unstable vital signs or high clinical suspicion for hemorrhage within 8 hours of injury
Randomized to TXA versus placebo
One gram over 10 minutes followed by a second one gram infusion over 8 hours
Unstable VS: SBP< 90 mmHg, HR > 110 bpm or both

11. CRASH 2 Analyses Summary Results
Decreased all-cause mortality 16.0% to 14.5%, NNT 67
Decreased risk due to bleeding 5.7% to 4.9%, NNT 121
Greatest reduction in deaths due to bleeding:
Severe shock (≤ 75 mmHg) 14.9% vs 18.4%
Within first hour - benefit seen within 3h of injury
Increased risk of death if administered after 3 hours
TXA not associated with ↑ vascular occlusive events
TXA safe and effective across all mortality groups
In the subgroup of trauma patients presenting with SBP of 75 mm Hg or less, all-cause 28 day mortality was 30.6% for the TXA group versus 35.1% for the placebo group.
Risk of death from any cause: TXA 14.5% vs 16.0%; RR 0.91; 95% CI, ; p =
Risk of death caused by bleeding: TXA 4.9% vs 5.7%; RR 0.85; 95% CI, ; p=0.0077
Exploratory Analysis of CRASH-2: Early Versus Late TXA
Subgroup analysis confirmed a significant reduction (19%) in deaths caused by bleeding (14.9% vs 18.4%; RR 0.81; 95% CI, ) in the most severe hemorrhagic shock patients with SBP of 75 mmHg or less.
Early TXA treatment (≤ 1 hour from injury) was associated with the greatest reduction (32% reduction) in deaths caused by bleeding (198[5.3%] of 3,747 for the TXA group vs 286[7.7%] of 3,704 for the placebo group; RR 0.68; 95% CI ; p<0.0001).
Treatment given between 1-3 hours after injury also reduced the risk of death caused by bleeding (147[4.8%] of 3,037 vs. 184[6.1%] of 2,996; RR 0.79; 95% CI , p = 0.03)
TXA AFTER 3 hours of injury was associated with an increased risk of death caused by bleeding (144[4.4%] of 3,272 vs 103[3.1%] of 3,362;RR 1.44 CI , p =0.004).

12. Retrospective, observational Military environment
Overall: AR 7.6%, 6.5%
MT: AR 13.7%, RR 49% OR for survival [95% CI 3.0 to 17.3]
The authors concluded that the use of TXA after combat injuries improves survival among all patients requiring transfusion and most prominently among patients requiring massive transfusion.

13. TXA Is Cost Effective

14. One dose TXA costs ~ $ $65
One dose Factor VIIa costs ~ $8500

15. Adverse Effects Seizures (perioperative - high dose)
Rapid infusion hypotension
Thromboembolism
no difference between groups in CRASH 2
not seen in pediatric surgery (high doses)
systematic reviews have not found a concern
Very rare
Thrombotic complications have been described. Cannot be used with prothrombin complex concentrate or recombinant activated Factor VII.
Henry et al Cochrane Review 2011
Ker et al BMJ 2012,
Faraoni D, Goobie SM Anesth Analg 2014

16. Ideal hemostatic Agent
Easy to store and use
Stops inappropriate hemorrhage
Does not clot working vessels
No side effects (minimal)
Free (cheap)
TXA easy to administer and to store, and does not require refrigeration or reconstitution prior to its administration.
Richard Dutton EMCrit Conference 2011

17. Knowledge Gaps Use in significant traumatic brain injury? (CRASH 3)
Optimal dosing?
Mortality benefit in advanced trauma systems (PATCH) Emerg Med Aust 2014, J Trauma Acute Care Surg 2014
“True” risk of thromboembolism?
Role of fibrinolysis testing prior to giving TXA?
Indications in pediatric trauma?
Thromboembolism:
Was it looked for?
interaction with other medications? Factor VII
Elderly
In flight risk of venous thromboembolism

19. Pediatric Trauma Differences & Similarities
Broad anatomic, physiologic, developmental age spectrum
Different hemodynamic response
Blunt >> penetrating
Low operative rates
TBI common in both
Beno et al. Crit Care 2014

20. Pediatric Trauma Coagulopathy
ATC is prevalent in pediatric trauma (27, 38, 77%)
ATC strongly associated with ↑ mortality in children (civilian and in combat support hospitals) OR 2.2
TBI and early coagulopathy significantly ↑ mortality (fourfold)
Hendrickson (J Pediatr 2012) demonstrated coagulopathy is prevalent in pediatric trauma patients ill enough to require a transfusion and is strongly associated with mortality. (Atlanta)
102 children (mean 6y, ISS 22, GCS 7, 80% blunt)
Abnormal CCTs (%): PT 72, PTT 38, Fib 52, Hg 58, Plt 23 strongly associated with mortality
744 patients (9y, 17% blunt) in combat hospitals early coagulopathy: 27% OR for mortality shock: % OR for mortality pediatric civilian trauma patients early coagulopathy 37.9% - 4fold ↑ with TBI
Hendrickson et al. J Pediatr Surg Patregnani et al. Pediatr Crit Care Med Whittaker et al. Shock 2013

21. Pediatric Trauma Hyperfibrinolysis
not clearly described
Fibrinogen levels low in 52% of children needing transfusion [20% < 100 mg/dL]
rTEG in pediatric trauma
Hendrickson et al. J Pediatr Surg Vogel etal. J Pediatr Surg 2013

22. Pediatric Trauma TXA makes sense!
Hemorrhage, like in adults, is the second leading and main preventable cause of traumatic death
Trauma-associated coagulopathy exists in kids
Hyperfibrinolysis - very likely
Track record of safety and efficacy when used in HIGH doses in pediatric surgery
Healthier vascular systems

24. Pediatric Trauma Practical Considerations
Intraosseous route (no data)
Pre-hospital administration (by age?)
Adolescents and children (different)
Careful prospective monitoring

27. Prospective pediatric RCT in
developed trauma systems on a global scale

28. TXA in Trauma
TXA reduces mortality in bleeding adult trauma patients if given within 3 hours of injury, and is not associated with increased thrombotic complications.
TXA is cost-effective.
Knowledge translation is needed Knowledge gaps do exist.
TXA safely used in pediatric surgical patients, adult trauma patients, and most likely safe/effective for pediatric trauma patients. Further research needed.

29. Questions?