Use of Antifibrinolytics in Pediatric Life-Threatening Hemorrhage: A Prospective Observational Multicenter Study

Abstract

OBJECTIVES: To assess the impact of antifibrinolytics in children with life-threatening hemorrhage. DESIGN: Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four children’s hospitals in the United States, Canada, and Italy. PATIENTS: Children 0–17 years old who received greater than 40 mL/kg of total blood products over 6 hours or were transfused under activation of massive transfusion protocol. Intervention/Exposure: Children were compared according to receipt of antifibrinolytic medication (tranexamic acid or aminocaproic acid) during the bleeding event. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, medications administered, and clinical outcomes were analyzed using Cox proportional hazard and Kaplan-Meier survival analysis. The primary outcome was 24-hour mortality. Of 449 patients analyzed, median age was 7 years (2–15 yr), and 55% were male. The etiology of bleeding was 46% traumatic, 34% operative, and 20% medical. Twelve percent received antifibrinolytic medication during the bleeding event (n = 54 unique subjects; n = 18 epsilon aminocaproic acid, n = 35 tranexamic acid, and n = 1 both). The antifibrinolytic group was comparable with the nonantifibrinolytic group on baseline demographic and physiologic parameters; the antifibrinolytic group had longer massive transfusion protocol duration, received greater volume blood products, and received factor VII more frequently. In the antifibrinolytic group, there was significantly less 6-hour mortality overall (6% vs 17%; p = 0.04) and less 6-hour mortality due to hemorrhage (4% vs 14%; p = 0.04). After adjusting for age, bleeding etiology, Pediatric Risk of Mortality score, and plasma deficit, the antifibrinolytic group had decreased mortality at 6- and 24-hour postbleed (adjusted odds ratio, 0.29 [95% CI, 0.09–0.93]; p = 0.04 and adjusted odds ratio, 0.45 [95% CI, 0.21–0.98]; p = 0.04, respectively). CONCLUSIONS: Administration of antifibrinolytic medications during the life-threatening event was independently associated with improved 6- and 24-hour survivals in bleeding children. Consideration should be given to use of antifibrinolytics in pediatric patients with life-threatening hemorrhage.

Bringing Hidden Biases Into Light: Comments on an Observational Study on the Use of Antifibrinolytics for Pediatric Patients With Life-Threatening Hemorrhage

“…Second, the study by Spinella et al (1) did not consider the heterogeneity of each hospital. Because this was an observational study, hospital-related factors, such as severity of hemorrhage, ICU care, and mortality rates in patients that are critically ill, might vary at each participating hospital.…”

Tranexamic Acid in Pediatric Hemorrhagic Trauma

“…33 In a secondary analysis of the population receiving antifibrinolytics, they found that TXA or epsilon-aminocaproic acid was independently associated with improved 6-and 24-hour survival in bleeding children. 32 This study included 449 patients from 24 centers with bleeding for any reason, 207 had traumatic injury, and 54 received TXA. After adjusting for Pediatric Risk of Mortality score in a Cox proportional hazard model, TXA decreased 6-hour mortality with an odds ratio of 0.29 (95% CI, 0.09-0.93).…”

“…To review, three of the five pediatric studies evaluated indicated an association of TXA with improved mortality. 28,31,32 Two of these were in combat populations and adjusted for injury severity. 28,31 The other, the MATIC trial, was a civilian prospective study and adjusted for relevant confounders.…”

Preface: Pediatric traumatic hemorrhagic shock consensus conference

“…Mortality in children with traumatic hemorrhagic shock is between 36% and 50% based on recent studies 3,4 . Recent retrospective and prospective observational studies indicate that resuscitation practices (limiting crystalloid, appropriate blood product ratios, use of whole blood, and tranexamic acid use) can dramatically reduce morbidity and mortality in children with traumatic hemorrhagic shock 5–9 . Because of these alarming statistics, resuscitation and hemostatic strategies are a key target for standardization and subsequent investigation.…”

“…3,4 Recent retrospective and prospective observational studies indicate that resuscitation practices (limiting crystalloid, appropriate blood product ratios, use of whole blood, and tranexamic acid use) can dramatically reduce morbidity and mortality in children with traumatic hemorrhagic shock. [5][6][7][8][9] Because of these alarming statistics, resuscitation and hemostatic strategies are a key target for standardization and subsequent investigation. However, clinical trial design surrounding this topic would be very difficult because of not only the lack of standardization in resuscitation approaches, transfusion strategies, utilization of hemostatic monitoring, and adjuncts but also the lack of agreed upon critical definitions and common data elements for study.…”