Pediatrics

Effectiveness and safety of tranexamic acid in pediatric trauma: A systematic review and meta-analysis

a b s t r a c t

Objective: Trauma is the leading cause of childhood death in the United States. Our goal was to determine the effectiveness of tranexamic acid in improving survival in pediatric trauma.

Methods: MEDLINE (OVID), Embase (OVID), Cochrane Central Register databases, CINAHL (EBSCO), Web of Science (Clarivate Analytics), and grey literature sources were searched for publications reporting survival and safety out- comes in children receiving TXA in acute trauma, with no language restrictions, published until February 11, 2021. Two independent researchers assessed studies for eligibility, bias, and quality. Data on the study setting, injury type, participants, design, interventions, TXA dosing and outcomes were extracted. The primary outcome was sur- vival in children who received TXA following trauma. Forest plots of effect estimates were constructed for each study. Heterogeneity was assessed and data were pooled by meta-analysis using a random-effects model.

Results: Fourteen articles met inclusion criteria – six single-institution and eight multicentre retrospective cohort studies. Overall, TXA use was not associated with increased survival in pediatric trauma (adjusted odds ratio [aOR]: 0.61, 95% CI: 0.30-1.22) after adjustment for patient-level variables, such as injury severity. Increased sur- vival was documented in the subset of children experiencing trauma in combat settings (aOR for mortality: 0.31, 95% CI: 0.14-0.68). There were no differences in the odds of Thromboembolic events (OR 1.15, 95% CI: 0.46-2.87) in children who received TXA versus not.

Conclusions: The utility of TXA in children with trauma is unclear. Guidelines supporting TXA use in pediatric trauma may not be based on the available evidence of its use in this context. Rigorous trials measuring survival and other meaningful outcomes and exploring optimal TXA dosing are urgently needed.

Study Registration (PROSPERO): CRD42020157683.

(C) 2022

  1. Introduction
    1. Background and importance

Trauma is the leading cause of pediatric deaths in the US, and other highly-resourced countries, claiming the lives of >12,000 children in

* Corresponding author at: Division of Pediatric Emergency Medicine, Department of Pediatrics, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada

E-mail address: [email protected] (Y. Finkelstein).

1 Co-Senior authors.

the US each year- more than all other causes of pediatric death com- bined [1]. Roughly 150,000 injured children each year require hospital- ization and most have long-term sequelae [2]. Death in pediatric trauma is primarily due to direct injury to critical organs (e.g., brain, lungs) or hemorrhage into the brain, thoracic or abdominal cavities [3]. Hemor- rhage may worsen through development of coagulopathy, which is an independent predictor of associated death [4]. Thus, hemorrhage is the most preventable cause of death in children with trauma. Despite the substantial impact of trauma on children, there are no medications for injured children that have been proven to decrease mortality or im- prove overall outcomes.

https://doi.org/10.1016/j.ajem.2022.01.069

0735-6757/(C) 2022

tranexamic acid is an antifibrinolytic agent that attenuates bleeding through inhibition of plasmin formation, and is safely used to control bleeding and lower transfusion needs in various conditions in children and adults [5-10]. Recent evidence suggests additional benefits via modulation of the inflammatory response [11]. The landmark CRASH-2 randomized clinical trial (RCT) demonstrated that TXA de- creased hemorrhagic death by one-third in severely injured adults [12]. A recent systematic review has reported an even greater mortality reduction [13]. However, children have different injury mechanisms, physiologic responses to injury, and possibly different response to TXA, than adults. Due to the absence of a parallel pediatric trials more than a decade after the publication of CRASH-2, TXA use in injured chil- dren has been sporadic, unsupported by rigorous evidence, potentially denying many injured children a life-saving therapy [14].

Professional societies have taken different stances on TXA use in pe- diatric trauma. While the American Academy of Pediatrics and the Ca- nadian Paediatric Society have no formal statements, the United Kingdom’s (UK) Royal College of Paediatrics and Child Health released a position statement [15] in 2012, recommending TXA use in pediatric trauma. This recommendation was based on extrapolation from adult data, and the general efficacy and safety data from other pediatric indi- cations for TXA, such as planned cardiac, orthopedic or craniofacial sur- geries [16,17]. However, there have been no comprehensive systematic reviews or meta-analyses to evaluate TXA use for pediatric trauma. Sub- sequently, in a survey of pediatric massive blood transfusion protocols including 15 major UK trauma centers and the UK Defense Medical Ser- vice, only two protocols recommended against the use of TXA in chil- dren [18].

    1. Goals of this investigation

As a critical step to close the knowledge gap, and in response to expert calls [19] to determine the role of TXA in pediatric trauma, we conducted a systematic review and meta-analysis of all published and unpublished data on the effectiveness and safety of TXA in the setting of pediatric trauma. The primary outcome was survival in children who received TXA following trauma.

  1. Methods
    1. Search methodology

Our systematic review focused on the efficacy and safety of TXA in children 0-18 years with acute hemorrhage from traumatic injury (PROSPERO registration: CRD42020157683). An experienced health sci- ences librarian (LYR) developed the search strategy, which combined relevant MeSH terms and keywords related to the use of TXA for hemorrhage in Pediatric trauma patients. The final search included MEDLINE (OVID), Embase (OVID), Cochrane Central Register databases, CINAHL (EBSCO), and Web of Science (Clarivate Analytics), as well as grey literature sources from inception until February 11, 2021. Grey lit- erature was searched by looking at registered controlled trials (ClinicalTrials.gov, WHO, International Clinical Trials Registry Platform (ICTRP), Canadian Clinical Trials Database). Additional searches were conducted in the New York Academy of Medicine Grey Literature Report, FDA website (http://www.fda.gov/drugs/drugsafety/default. htm), the OpenGrey (www.opengrey.eu/), Google Scholar and the Canadian Agency for Drugs and Health Technologies (http://cadth.ca/ en/products). Separate handsearching using key terms and snowball searching (i.e., using the reference list of a paper to identify additional papers) using relevant articles was conducted. Lastly, we reached out to experts in the field, scanned the reference lists of included studies and related systematic reviews, reviewed expert opinion publications and relevant commentaries for additional articles. No restrictions were placed on language, year, format or publication status. The search strat- egy is detailed in eSupplement I.

All study types which evaluated the use of TXA in trauma patients

<18 years were eligible for inclusion. While case reports were excluded, case series (two or more patients) were included. Studies were included regardless of the type of trauma, route of TXA administration, or the set- ting of TXA administration. No control group was required, and all types of comparators were included. No specific outcome measures were re- quired for inclusion. Studies were excluded if they focused on the use of TXA in elective surgery or were conducted in patients with underly- ing Bleeding disorders. Studies of both pediatric and adult patients were included if pediatric specific data were available. If it was unclear if the study population included children, we attempted to contact the corresponding authors via email, up to three attempts, to determine if children were included and if so, if pediatric specific data could be pro- vided. Articles were uploaded into Covidence (https://www.covidence. org) for screening and review. All records were independently screened by two reviewers (EK, MR), first by title and abstract, then by full articles and texts, and conflicts were resolved by discussion. If consensus was not reached, a third reviewer (YF or PJG) made a final decision. Data ex- traction forms were developed a priori, and data were extracted by one reviewer and verified by a second reviewer. Key aspects of the data extraction form included study type, participant demographics (e.g., age, sex), injury circumstances (e.g., type of trauma), intervention (e.g., TXA route, dose, co-interventions, comparison groups), outcomes (e.g., death, surgery), and other key determinants. For studies including both adults and children, only pediatric specific data were extracted. The quality of included studies was assessed independently by two re- viewers (EK, PJG) using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool, and conflicts were resolved through dis- cussion [20]. The quality of the evidence was assessed using Cochrane groups GRADE (Grading of Recommendations, Assessment, Develop- ment and Evaluations) tool [21].

    1. Statistical analysis

We planned a priori to conduct a meta-analysis if studies were suffi- ciently homogeneous, such that comparisons were meaningful, segre- gated by study type. For dichotomous outcomes, odds ratios (OR) or risk ratios (RR) are presented, while for continuous outcomes, a stan- dardized mean difference was calculated. Forest plots of effect estimates were constructed for each study to illustrate key study findings. Hetero- geneity was assessed clinically by comparing individual study charac- teristics (i.e., study participants, Inclusion/exclusion criteria and outcomes), methodologically by comparing design characteristics and risk of bias assessment, and statistically using I2. For studies that had similar clinical study populations and acceptable statistical heterogene- ity (defined as I2 statistic below 60%), we conducted a meta-analysis using a random-effects model. For statistical analysis, we used Review Manager software 5.4 to calculate standardized mean difference or risk ratios. Overall significance for study outcomes was set at a p-value of 0.05 (two-sided).

  1. Results
    1. Search results

The initial search yielded 4069 unique titles after removing dupli- cates, of which 3946 were excluded after screening based on title and abstract (Fig. 1). We contacted the corresponding authors of 26 of the 123 remaining studies to determine if pediatric specific data could be available, of whom three provided usable pediatric data, while others had no pediatric patients or did not respond. A total of 22 studies met inclusion criteria. Multiple reports of individual studies were collated, leading to 14 unique studies (Table 1). Studies were conducted in seven countries and were published between 1977 and 2021. Nine

were retrospective cohort studies, four retrospective reviews of admin- istrative databases, and one was a case series. Eleven studies explored the efficacy and safety of TXA use in pediatric trauma – six evaluated combat trauma and five were conducted in civilian hospitals, while three focused on TXA use in isolated eye trauma (traumatic hyphema) and were evaluated separately. The risk of bias assessment is reported in the Supplemental Figure.

    1. General pediatric trauma
      1. Combat trauma

Four retrospective studies conducted in combat settings reviewed trauma registry databases from Iraq and Afghanistan (three full texts, one abstract) and two reviewed data from the Israeli Trauma Defense Registry. One study of 4358 children observed increasing TXA use over the study period (2001 to 2013), but did not explore patient outcomes [22]. Two studies used the Israeli Trauma Defense Registry, one reported data from 2013 [23] and the other reported data from 2013 through 2016 [24]. Overall, 350 pediatric patients were included, of whom 45 re- ceived TXA but pediatric outcome data was not available [23,24]. The re- maining three studies compared outcomes in children receiving TXA versus not, including 1758 children, of whom 190 received TXA and 1568 served as controls (Table 1) [25-27]. Common types of injuries in- cluded blasts, penetrating and blunt trauma [25,26].

Of the three studies comparing outcomes of TXA use to Standard care for pediatric trauma [25-27] all found that TXA was more frequently ad- ministered to children with more severe injuries and worse baseline prognostic factors. Booth et al. reported no difference in mortality rates between children receiving TXA and controls (OR 1.45, 95% CI 0.76-2.76), including in a subgroup analysis of those with severe trau- matic brain injuries (24% vs. 43% [p = 0.06]) or injury severity score

(ISS) >15 (27% vs. 38% [p = 0.18]) [27]. After adjusting for mechanism, ISS, serum Base deficit, hypotension, and GCS score, Eckert et al. re- ported that TXA use was associated with decreased mortality (adjusted odds ratio [aOR] 0.27, 95% CI 0.08-0.87; Fig. 2) [25]. Hamele et al. also found that TXA use was associated with decreased mortality after con- trolling for age, sex, head component of Abbreviated Injury Scale, serum base deficit, and mechanism of injury (aOR 0.35, 95% CI 0.12-0.99; Fig. 2) [26]. In a meta-analysis of the adjusted results we found that TXA was associated with decreased mortality in pediatric combat trauma (1273 participants; OR 0.31, 95% CI: 0.14-0.68, Fig. 2). In unadjusted models, Hamele et al. found no difference in other clinical outcomes including ventilator-free days and ICU free days [26] while Eckert et al., using propensity matched analysis, found that TXA use was associated with decreased need for mechanical ventilation (6% vs. 22%; p = 0.01) and improved neurologic status at discharge (discharge GCS <9: 10% vs. 31%, p = 0.04) [25]. Only Eckert et al. explored adverse events secondary to TXA use, and reported no thromboembolic events or seizures in either group, but noted an increased likelihood of blood transfusion in children receiving TXA (OR 14.98, 95% CI 7.28-30.82), which may be confounded by severity [25].

      1. Civilian trauma

Five retrospective cohort studies explored the use of TXA in injured children in civilian hospitals, two in the United States (US) [28,29], two in the United Kingdom [30,32], and one in Japan [31].

Nishijima et al. found that in 35,478 instances of TXA use in US children’s hospitals, trauma was the indication in only 110 (0.31%) [28]. Maeda et al. found children were more likely to re- ceive TXA if they had a head or torso injury, had an Ambulance transfer to hospital, were treated at a hospital with >400 beds, or at an academic hospital [31]. Ageron et al. [32] used data from the Trauma Audit Research Network (2017-2018) to validate a

Records after duplicates removed (n = 4069)

Additional records identified through other sources

(n = 0)

Records identified through database searching

(n = 58)

Full-text articles assessed for eligibility

(n = 123)

Records screened (n = 4069)

Records excluded (n = 3946)

Full-text articles excluded, with reasons

(n = 109)

Fig. 1. PRISMA flow diagram.

Studies included in qualitative synthesis (n = 14)

Table 1

Descriptive summary of included studies.

Study type Duration Study population Comparisons

(n = number of subjects/patients)

TXA dosing regime Outcomes

Traumatic Hyphema

Albiani 2008

Deans 1992

Uusitalo 1988

Retrospective cohort

Retrospective Cohort

Retrospective cohort

Not reported

Jan

1977-Dec

1990

Jan

1975-Feb

1987

Age <= 17, traumatic hyphema acquired through blunt trauma

Total = 215

Age <= 17, traumatic hyphema caused by non-penetrating blunt trauma

Total = 479

Age <= 17, non-perforating traumatic hyphema

Total = 340

TXA + topical steroids

(n = 137) Topical steroids alone (n = 78)

TXA + topical steroids (n = 163)

Topical steroids alone (n = 316)

TXA + bed rest (n = 26)

TXA + ambulation (n = 95)

No TXA, strict bed rest, binocular patching and sedation (n = 219)

25 mg/kg 3 times per day for 5 days PO visual acuity, rebleed rate, Intraocular pressure, time to hyphema

resolution, hyphema grade, need for medications to lower intraocular pressure, presence of associated complications

25 mg/kg (max 1.5 g) every 8 h for 5 days Secondary hemorrhage, intraocular pressure, length of hospital stay,

changes in visual acuity, side effects of TXA

25 mg/kg 3 times a day for 3-5 days PO Secondary hemorrhage, visual acuity, time of clotted blood in anterior

chamber, length of hospital stay, development of cataract

Combat trauma

Benov 2019

Bitterman 2013

Booth

2015a

Cannon 2018

Eckert 2014

Retrospective cohort

Retrospective cohort

Retrospective cohort Retrospective cohort Retrospective cohort

2013-2017 Any ageb, traumatic injury, receiving pre-hospital treatment from the Israeli Defense Force Medical Corps

Total = 350

2013 Any ageb, traumatic injury, receiving pre-hospital treatment from the Israeli Defense Force Medical Corps

Total = 135

2006-2013 Age <= 16, traumatic injury

Total = 485

2001-2013 Age < 18, traumatic injury

Total = 4358

2008-2012 Age < 18, traumatic injury

Total = 766

TXA (n = 43)

No TXA (n = 307)

TXA (n = 6)

No TXA (n = 129)

TXA (n = 65)

No TXA (n = 420) TXA (n = 98)

No TXA (n = 4260) TXA (n = 66)

No TXA (n = 700)

1 g IV pre-hospital Not stated

1 g IV pre-hospital Not stated

  • Patterns of TXA use, mortality
  • Not stated

1 g IV bolus <3 h of injury Survival, complications of TXA

Hamele 2020

Retrospective cohort

2006-2013 Age < 18, received massive transfusion (>=40 ml/kg all blood product) within 24 h of injury

Total = 507

TXA (n = 59)

No TXA (n = 448)

1 g < 3 h of injury, then 1 g over 8 h at discretion of team

In hospital mortality, 24-h mortality, blood products transfused, hospital free days, ICU free days, ventilator free days

Civilian trauma

Ageron 2021

Retrospective Cohort

2017-2018 Any ageb, ISS > 8, admitted to hospital for 3 or more nights or transferred for specialist care, or died in hospital

Total = 6379

TXA (n = 938)

No TXA (n = 5441)

Mean 812.3 mg (SD 410.3) Validation of Bleeding Audit and Triage Trauma Score – BATT

Maeda 2018

Retrospective cohort

Jul

2010-Mar

2014

Age <= 12, trauma as main diagnosis, received a blood transfusion

Total = 3828

TXA (n = 1914) No TXA (n = 1914)

  • In hospital mortality, adverse effects (seizure, thromboembolism, renal dysfunction)

Marsden 2019

Retrospective Cohort

2017 Adult and pediatric trauma admissions who received TXA following their injury

Total encounters (n = 661)

Pediatric (n = 68)

  • Time interval from injury to TXA administration

Nishijima 2016

Retrospective cohort

Jan 1, 2009

– Dec 31,

2013

Age < 18, received TXA, no underlying hemophilia or factor deficiencies

Total encounters (n = 35,478)

TXA for traumatic injury (n = 110)

– Overall use of TXA, use of TXA for trauma

Thomson 2021

Retrospective Cohort

Aug

2011-Mar

2019

Age <= 16 years, massive transfusion protocol ordered for trauma, dose of TXA properly recorded

Total = 48

TXA (n = 29) No TXA (n = 19)

15 mg/kg loading dose over 10 min (max 1 g), then 2 mg/kg/h infusion for 8 h (maximum 1 g) if indicated

Survival to hospital discharge, surgical intervention, type of blood product transfused, volume of blood products transfused, length of stay, thrombosis

PO = Oral; IV = Intravenous. TXA = tranexamic acid, ISS = injury severity score.

E. Kornelsen, N. Kuppermann, D.K. Nishijima et al.

American Journal of Emergency Medicine 55 (2022) 103110

106

– = data not reported.

a Abstract only.

b Study included any age, data included in table is from subset of pediatric patients.

Table 2

Summary of outcome data reported in included studies (n =5 studies).

Booth 2015

Eckert 2014

Hamele 2020

Maeda 2018

Thomson 2021

TXA

No TXA

TXA

No TXA

TXA

No TXA

TXA

No TXA

TXA

No TXA

Demographics

Age

<=16

<=16

11 (SD 4)

11 (SD 5)

10 (IQR 5-13)

9 (IQR 5-12)

7 (4-9)

7 (4-9)

14 (IQR 12-16)

11 (IQR 4-14)

Sex (% Male)

NR

NR

57 (86%)

617 (88%)

48 (81%)

327 (73%)

1252 (65.4%)

39,331 (65.7%)

23 (79%)

11 (58%)

Outcomes

Death

14 (21.5%)

67 (16%)

10 (15%)

5 (8%)

5 (8.5%)

83 (18.3%)

13 (0.68%)

18 (0.94%)

10 (34%)

5 (26%)

Blood transfusion after TXA

NR

NR

57 (85%)

208 (30%)a

59 (100%)

448 (100%)

NR

NR

29 (100%)

19 (100%)

Surgical intervention

NR

NR

61 (92%)

522 (74%)

NR

NR

NR

NR

20 (67%)

16 (84%)

Clotting events

NR

NR

0

0

NR

NR

1 (0.05%)

2 (0.1%)

4 (14%)

3 (16%)

Adverse events

NR

NR

0

0

NR

NR

10 (0.52%)b

0%

4 (14%)

3 (16%)

NR not reported, SD standard deviation, IQR interquartile range Note: Data from Canon 2018, Nishijma 2016 and Shkrupii 2018 are not included in this table as they explored single cases or case series and did not including data comparing outcomes in patients receiving TXA relative to those who did not. Marsden 2019 is not included at this study explored timing of TXA administration rather than effects of TXA administration.

a Unclear if transfusion was given before or after administration of TXA.

b Seven experienced seizure and three experienced renal dysfunction.

Bleeding Audit and Triage Trauma Score – BATT. A total of 6379 pe- diatric patients were included in this database, of whom 938 re- ceived TXA. Frequency of TXA use increased with age, from only 2% of trauma patients 0 to 2 years up to 28.5% of patients 16 to 18 years. Of those who received TXA, 48 (5.1%) died due to hemor- rhage and 87 (9.3%) died of any cause within 30 days.

Only two studies directly compared outcomes in patients treated with TXA versus no TXA in civilian settings [29,31], and neither found a difference in mortality between the groups (aOR 0.72, 95% CI 0.35-1.48 [31]; aOR 1.41, 95% CI 0.61-3.24 [29], respectively,

Fig. 2). In a meta-analysis of these two studies, we found no differ- ence in mortality (3876 participants: OR 0.97, 95% CI: 0.51-1.87;

Fig. 2).

      1. TXA and survival following pediatric trauma in all settings combined Overall, combining studies performed in combat and civilian set- tings, there was no association between TXA use and pediatric mortality post trauma (four studies; 5149 participants; OR 0.61, 95% CI: 0.30-1.22; Fig. 2). Further, Maeda et al. [31] did not find a difference in ICU admission rates between the TXA and non-TXA groups (aOR

1.13, 95% CI 0.83-1.54; Fig. 3 and Table 2).

    1. TXA-related adverse events

We also assessed key Safety outcomes. No difference was observed in the rate of thromboembolic events with TXA administration by Maeda et al. (OR 0.50, 95% CI: 0.05-5.25 [31], Fig. 3) Thomson et al. (OR 1.33,

95% CI: 0.49-3.60 [29], Fig. 3), or in a meta-analysis of these two studies (OR 1.15, 95% CI: 0.46-2.87, Fig. 3). Eckert et al. [25] reported no thrombo- embolic events in either study arm. Rates of surgery in patients who re- ceived TXA were higher in the study of Eckert et al. (OR 4.16, 95% CI 1.65-10.50, Fig. 3) but not in that performed by Thomson et al. (OR 0.42, 95% CI 0.10-1.78, Fig. 3 and Table 2). Due to significant statistical heterogeneity (I2 85%), a meta-analysis was not conducted. Maeda et al. also reported that while TXA was not associated with renal dysfunction, a small absolute increase in seizure risk was observed (absolute risk in- crease: 0.37%, 95% CI: 0.10-0.64) [31]. Two studies assessed the associa- tion of TXA use with abdominal cramps, nausea, vomiting and diarrhea, and neither found any events in the treatment or control groups [34,35].

    1. Traumatic hyphema in children

Three retrospective studies evaluated the use of TXA in traumatic hyphema in children and included a total of 1034 participants, of

Image of Fig. 2

Fig. 2. Meta-analysis of mortality outcome in included studies (n = 4).

*Adjusted for mechanism, injury severity score (ISS), serum base deficit, hypotension, and Glasgow Coma Scale score.

**Adjusted for age, sex, head component of abbreviated injury scale, serum base deficit, and mechanism of injury.

***propensity matching based on age, gender, body weight, height, trauma sites, hospital type, PICU admission, ambulance transfer, and hospital volume.

****Adjusted for age and gender.

Image of Fig. 3

Fig. 3. Meta-analysis of key clinical and safety outcomes in included studies (n = 3).

*Propensity matching based on age, gender, body weight, height, trauma sites, hospital type, PICU admission, ambulance transfer, and hospital volume.

**Unadjusted.

***Adjusted for age and gender.

whom 421 received TXA and 613 did not. We evaluated these studies separately from those of general pediatric trauma. All three studies of traumatic hyphema were conducted in pediatric hospitals, two in Canada [33,34] and one in Finland [35]. For all three studies, the TXA dose was 25 mg/kg, 3 times per day, and the duration of administration varied from 3 to 5 days. The two older studies of inpatient children (published in 1988 [35] and 1992 [26]) found that addition of TXA to corticosteroids in traumatic hyphema led to decreased rates of hyphema rebleeding compared to corticosteroids alone (0.8% vs. 9.6%, p< 0.01 [35]; 3.0% vs. 0.8%, p < 0.01 [34]), while a 2008 study in an out- patient setting failed to demonstrate a difference in rebleeding rate (1.6% vs. 2.6%, p = 0.60) [33].

  1. Discussion

In this systematic review and meta-analysis on the efficacy and safety of TXA in pediatric trauma, we identified 14 unique retrospective studies published between 1977 and 2021. Eleven reported TXA use in general pediatric trauma, and three in traumatic hyphema. Overall, lim- ited evidence suggests Survival benefit of TXA in combat trauma, but not in civilian trauma, or when combined for trauma of any cause. Further- more, there is mixed, sparse evidence about the benefit of TXA for trau- matic hyphema in children.

The evidence on TXA effectiveness in pediatric trauma is of lesser rigor and is difficult to compare to the adult trauma literature, which demonstrated increased survival [12,36]. Pooled adult data based pri- marily on the CRASH-2 trial [12], CRASH-3 [36] and subsequent studies [37,38] including patients from more than 40 countries [39,40] cumula- tively favors TXA use, with mortality reduction of 10% in general adult trauma, but less conclusive in traumatic brain injury [41].

Our meta-analysis of two studies in combat settings [25-27] showed that children treated with TXA had increased survival, despite more se- vere injuries and worse prognostic predictors compared with those who did not receive TXA. Other patient-level outcomes (e.g., mechanical ventilation) were also superior in children who received TXA, after ad- justment for injury type, severity and other variables. Conversely, of the four studies of civilian pediatric trauma, two [29,31] compared

outcomes of those receiving TXA versus not, and both found no differ- ence in mortality, which was consistent in a meta-analysis.

Several reasons may explain the differences observed regarding TXA effect on survival in adult versus pediatric trauma, and in pediatric elec- tive surgery versus trauma, most are related to the strength of evidence. While adult trauma evidence is based on well-powered prospective clinical trials, there are few observational pediatric trauma studies only. Furthermore, the information on TXA dosing regimens in the pedi- atric studies is limited [22,24,27,28,30,31]. TXA dosing in children ranged widely from 15 mg/kg bolus with or without a 2 mg/kg/h infu- sion over 8 hours [29] to fixed doses of 1 g bolus [25] with or without a 1 g infusion over 8 h [26]. In elective pediatric surgery, the dosing reg- imens are even more varied, and range from 10 mg/kg loading dose followed by a 1 mg/kg/h to 100 mg/kg/h infusion [16,17]. The varied dosing regimens can significantly impact patient outcomes and the rate and magnitude of adverse events. Because only limited retrospec- tive evidence on TXA use in pediatric trauma is available [42], experts called to generate high quality research [19,43]. For now, some suggest extrapolating from adult studies, especially for adolescents older than 16 years [29,44]. Indeed, current studies of TXA in pediatric trauma tended to include older [29,30] and taller [31] children, which does not apply to young injured children.

Our findings regarding TXA safety in pediatric trauma are consistent with systematic reviews of TXA use in elective surgery of pediatric sco- liosis [17], cardiac [42] and other major surgeries [16,45]. Similarly to those [16,17], we observed no increased risk of thromboembolism, sei- zures or other adverse events. However, safety data from other clinical settings or populations may not be applicable to pediatric trauma. While the systematic reviews of pediatric trials found no increased sei- zure risk of TXA in elective operative settings [16,17], one study re- ported an increased seizure risk in pediatric trauma patients receiving TXA; notably, this study [31] was controlled for “head and Neck trauma” rather than traumatic brain injury, which can affect seizure risk [46].

Several study limitations merit mention. First, the quality of evi- dence reviewed was limited by the small number and observational na- ture of studies, outcome heterogeneity, limited information on TXA dosing, control for confounding factors, and co-interventions not being

balanced between the groups. Second, in some studies, the follow-up period started immediately after injury, rather than at the time of TXA administration. Lastly, few adult studies mentioned they were open to include adolescents 15 or 16 years or older, however, not all confirmed if they had patients younger than 18 years. Despite these limitations it is imperative to appreciate the fact that this is indeed the most compre- hensive and best available data to-date, therefore, the synthesis of data in our study is critically important. In real life, many institutions and several professional societies [15,18] have incorporated TXA in pe- diatric trauma protocols based on much less rigorous evidence. It is crit- ical to provide best evidence to inform practice of frontline clinicians managing both hospital and pre-hospital pediatric trauma.

The totality of available data from pediatric trauma and in civilian settings fails to show survival benefit of TXA. Limited evidence suggests increased survival in pediatric trauma in combat settings. The sparse data on TXA in pediatric trauma sharply contrasts the high-quality data from prospective adult trauma and pediatric elective surgery trials. Despite that, TXA has been touted and implemented in pediatric trauma guidelines by professional bodies [15,18]. Rigorous Prospective trials of TXA use in pediatric trauma including children of all ages are feasible and urgently warranted, to inform practice in this area and conclusively determine TXA’s utility, safety and optimal dosing in the leading cause of childhood death. Until higher quality, more conclusive evidence is available, our systematic review and meta-analysis should inform TXA use in pediatric trauma.

Author contributions

YF, PJG, NK and DN conceived and designed the study and designed the trial; YF obtained research funding. LYR conducted the formal liter- ature search. EK, LYR and MR conducted the literature search and data extraction. NK, DN, PJG and YF supervised the conduct of the study and Data interpretation. YF and PJG provided data abstraction oversight, including quality control. EK and PJG conducted the statistical analyses. EK drafted the initial manuscript, and all authors contributed substan- tially to its revision. YF takes responsibility for the paper as a whole.

Declaration of Competing Interest

The authors report no conflicts of interest.

Acknowledgements

We thank Drs. Max Marsden, Avi Benov and Francois-Xavier Ageron for providing pediatric data from their respective studies.

Yaron Finkelstein holds a Canada Research Chair in Pediatric Drug Safety and Efficacy (Tier 1). The study was supported in part by SickKids Foundation.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2022.01.069.

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