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

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

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.

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.

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

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

Tranexamic Acid First clinical trial using oral TXA published in 1968 - heavy menstrual bleeding - FDA 2009 Dental extractions with hemophilia reported in 1972 - 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

TXA in Trauma What’s the evidence?

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

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, 0.85-0.97; p = 0.0035 Risk of death caused by bleeding: TXA 4.9% vs 5.7%; RR 0.85; 95% CI, 0.76-0.96; 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, 0.69-0.95) 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 0.57-0.82; 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 0.64-0.97, 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 1.12-1.84, p =0.004).

Retrospective, observational Military environment Overall: AR 7.6%, 6.5% MT: AR 13.7%, RR 49% OR for survival 7.228 [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.

TXA Is Cost Effective

One dose TXA costs ~ $5.40 - $65 One dose Factor VIIa costs ~ $8500

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

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

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

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

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 2.2 shock: 38.3% OR for mortality 3.0803 pediatric civilian trauma patients early coagulopathy 37.9% - 4fold ↑ with TBI Hendrickson et al. J Pediatr Surg 2012 Patregnani et al. Pediatr Crit Care Med 2012 Whittaker et al. Shock 2013

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 2012 Vogel etal. J Pediatr Surg 2013

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

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

Prospective pediatric RCT in developed trauma systems on a global scale

TXA in Trauma - 2014 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.

Questions?