Article, Traumatology

Evaluation of tranexamic acid in trauma patients: A retrospective quantitative analysis

a b s t r a c t

Introduction: Tranexamic acid has been shown to decrease mortality in adult trauma patients with or at significant risk of hemorrhage when administered within 3 h of injury. The use and appropriateness of TXA in adult trauma patients presenting to Royal Columbian Hospital (RCH) was investigated.

Methods: This retrospective chart review utilized the British Columbia Trauma Registry to identify 100 consecu- tive trauma patients that presented to the emergency department at RCH between April 2012 to June 2015 and met the following indications for TXA: systolic blood pressure b90 mm Hg and/or heart rate N110 bpm and pre- sentation within 8 h of injury. Primary outcomes included: percentage that met indications for TXA, received TXA according to the CRASH-2 protocol, received a pre-hospital dose, and received TXA <=1, N1 to <=3, or N3 h from in- jury.

Results: During the given time period, 117 subjects (2.7%) met indications for TXA. 67 patients (57%) received TXA in any dose, with 10 subjects (8.5%) receiving TXA according to the CRASH-2 protocol. Of the 67 patients who received any TXA, 76% did so <=3 h. 22 patients (19%) received TXA as a pre-hospital dose.

Conclusions: b10% of adult trauma patients that met the indication for TXA received it according to the CRASH-2 protocol. Of those patients that received TXA, 76% did so within 3 h. Further inquiry to identify reasons trauma patients are not receiving TXA as well as quality improvement initiatives in trauma care are required.

Level of evidence: III

Study type: Therapeutic

(C) 2018

  1. Introduction

Trauma is a major cause of mortality and the leading cause of death in those under 45 years old [1, 2]. Exsanguination is responsible for an estimated one-third of in-hospital mortality in trauma patients, with the most common sources being aortic, chest (heart and pulmonary) and pelvic trauma [3]. In current understanding, shock and tissue hypo- perfusion occur following trauma, initiating a state of systemic anticoagulation and hyperfibrinolysis which further exacerbates

? Authors would like to acknowledge Flora Young, Kathleen Fyvie, Joe Haegert and Iain MacPhail for their assistance during the course of this study. Authors declare no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. JP and SB proposed the study. MN collected data and drafted the manuscript. All authors were involved in study design, data interpretation, and critical revision.

* Corresponding author at: St. Paul’s Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.

hemorrhage [4, 5]. Acute coagulopathy occurs in almost 25% of trauma patients in hospital, and can increase mortality by four-fold [4-6]. It is reasonable to hypothesize then, that therapeutic agents that target fibri- nolysis could potentially minimize blood loss and mortality in trauma. Tranexamic acid1 (TXA) is an antifibrinolytic agent that reversibly inhibits the conversion of plasminogen to plasmin, thereby preventing interaction with fibrin and breakdown of fibrin clots [7]. It is included on the World Health Organization’s (WHO) list of essential medicines and is available in oral and intravenous (IV) form [8]. Current indica- tions include heavy menstrual bleeding, hereditary blood disorders, trauma, and surgery, in which it reduces post-operative blood loss and transfusions [7, 9]. Two systematic reviews and meta-analyses in an or- thopedic surgery population have shown no evidence of increased Thromboembolic events or other adverse effects versus controls [9]. TXA’s ability to decrease bleeding in varioUS settings, along with its tol- erability and inexpensive cost (less than $25 USD for a 1 g vial) has led

E-mail addresses: [email protected], (M. Ng), [email protected],

(J. Perrott), [email protected] (S. Burgess). 1 Tranexamic acid will be abbreviated as TXA.

https://doi.org/10.1016/j.ajem.2018.06.010

0735-6757/(C) 2018

to investigations of its use in trauma [9, 10]. (see Appendix A for supple- mental safety information).

In 2010, a randomized trial (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2, CRASH-2) of 20,211 adult trauma patients demonstrated that TXA 1 g administered IV over 10 min followed by 1 g IV over 8 h, when compared to normal saline IV, reduced all-cause mortality at 28 days from 16% to 14.5%, (RR 0.91, 95% CI 0.85-0.97, NNT 67). This was primarily driven by a decrease in hemorrhagic death from 5.7% to 4.9%, (RR 0.85, 95% CI 0.76-0.96, NNT 125) [11]. An exploratory analysis revealed that Mortality benefit was significant only when given within 3 h of injury, while unexpectedly, administration beyond 3 h increased bleeding death from 3.1% to 4.4% (p = 0.004, NNH 77). [12] No increase in vascular occlusive events or other serious adverse events was reported [11]. CRASH-2 has remained the primary evidence supporting use of TXA in trauma.

Royal Columbian Hospital (RCH) is a tertiary and regional referral hospital for the Lower Mainland in British Columbia, Canada. It is a level 1-trauma center and receives over 1000 trauma cases per year. Current use of TXA in trauma patients with actual significant hemor- rhage has not been previously evaluated. The objective of this retrospec- tive analysis was to characterize the use and appropriateness of TXA for adult trauma patients. The outcomes of this study will be utilized to identify care gaps and develop quality improvement initiatives in trauma care.

  1. Methods
    1. Study design

This was a retrospective chart review of the utilization of TXA in adult trauma patients. The study was conducted at Royal Columbian Hospital in New Westminister, British Columbia.

Population

A convenience sample of 100 adult trauma patients that presented to the emergency department at RCH with actual or suspected signifi- cant hemorrhage was chosen. The end date of the sample was June 2015, as this was the most recent data available at the time of the study. We worked retrospectively from this date until sample size was reached. Patients were included if they met the indications for TXA as specified in CRASH-2: trauma patient N16 years of age, significant hem- orrhage defined as systolic blood pressure b90 mm Hg and/or heart rate N110 bpm, and presentation within 8 h of injury. We did not include the CRASH-2 criteria of those “at risk of significant hemorrhage (i.e. com- pensated hemorrhage and stable vitals)” as it was not feasible to assess this retrospectively. Patients were excluded if they had a contraindica- tion to TXA (active myocardial infarction, clotting disorder, allergy) (See Appendix B for additional information on Inclusion/exclusion criteria).

Data collection or abstraction

One investigator abstracted data from the hospital records. Baseline demographics were collected using a standardized electronic data ex- traction form. A request to the BC Trauma Registry (BCTR) produced a report of trauma admissions from April 2012 to June 2015 that met criteria for age, vital signs, and presentation timeline, as well as demo- graphic information and a summation of total number of trauma admits during this period. This data was linked to hospital records, which were screened for inclusion based on whether patients were experiencing hemorrhage, and to collect outcome data. All information was recorded onto a password-protected spreadsheet by the investigator.

The study was completed under approval of the Fraser Health Re- search Ethics Board and in accordance with the Helsinki Declaration. As there was minimal risk to study subjects, consent was not required.

Fig. 1. Flow diagram of inclusion and exclusion of trauma population at Royal Columbian Hospital. *Excluded by initial BC Trauma Registry data request. See Methods section under ‘2.2 Population‘ and ‘2.3 Data collection or abstraction‘ for more detail on criteria.

Outcomes

The primary objective was to characterize utilization of TXA for trauma patients at a tertiary center. The secondary objective was to per- form an exploratory analysis of patient outcomes including in-hospital mortality, blood transfusions (number of units Packed red blood cells), vascular occlusions (deep vein thrombosis, pulmonary embolism, myo- cardial infarction, stroke), and surgical interventions.

Primary outcomes included: proportion of trauma patients that met indication criteria for TXA; proportion that received both doses as per CRASH-2 protocol (1 g IV/10 min bolus and 1 g IV/8 h infusion); propor- tion that received a pre-hospital dose; and for those that received TXA, proportion that received the medication within 1 h, 1 to 3 h, or N3 h from time of injury. These time categories reflect the classifications in CRASH-2 and the subsequent analysis that showed mortality benefit only when TXA was given within 3 h of injury [11, 12]. Secondary out- comes were defined as those that occurred during hospital stay up to 28 days as documented in patient chart, which reflects the time period used in CRASH-2.

Analysis

Descriptive statistics (e.g. percentages) were used to report and compare primary and secondary outcomes. For those that received

Table 1

Baseline demographics.

TXA, median time to treatment (with interquartile range IQR) and the percentages treated <=1, N1-<=3 or N3 h from time of injury was assessed. Average volume of blood transfused (units of packed red blood cells) with standard deviation was calculated. Fisher's Exact test was used to calculate odds ratio for mortality for TXA exposure, and timing of drug administration within 3 h versus N3 h. We utilized the Pearson Chi- square test to analyze secondary outcomes.

  1. Results

During this period, a total of 4328 trauma patients presented to RCH emergency department (Fig. 1). For the patients that were excluded ini- tially by the BCTR screening (n = 4034), we did not collect data on de- mographics, type of hemorrhage or clinical outcomes. Another 177 patients were excluded after review of hospital records. After review, 117 patients met inclusion criteria (Table 1). No patients had an identi- fied contraindication to TXA.

Baseline characteristics were generally similar between TXA and no-

TXA groups (Table 1). Mean age was 43 years old and 82% were male. Mean time from injury to presentation at emergency department was

1.2 h (SD 1.1 h). Eight patients presented beyond 3 h. The majority of patients (67 of 117; 57%) had a normal to mildly decreased GCS (13-15) on initial presentation, with most of those (42 of 67) having a GCS of 15. However more patients in the TXA group had a GCS score in the moderate (9-12) or severe (3-8) range. Mean systolic blood pres- sure and heart rate were both slightly higher in the no-TXA group. Mean Injury Severity Score was 26, which is considered profound

Combined (n =

Tranexamic acid (n

No tranexamic acid (n

trauma. A threshold of 15 is used for major trauma and constitutes a

117)

= 67)

= 50)

10% risk of mortality, 75 (maximum score) has an associated 100% risk

Sex Male

96 (82%)

54 (81%)

42 (84%)

of mortality [13].

The percentage of trauma admissions that met indication for TXA

Female

21 (18%)

13 (19%)

8 (16%)

was 2.7% (117/4328) (Table 2). Of the 117 included patients, 10 (8.5%)

Age (years) Mean (SD)

42.8 (18.9)

42.3 (17.9)

43.6 (20.4)

received both doses (bolus and infusion) as per the CRASH-2 protocol.

Alternate regimens were often used, such as 1 g over 30 min, 2 g over

b25

22 (19%)

10 (15%)

12 (24%)

60 min, 1.5 g bolus, and/or shorter infusion times. Eight subjects re-

25-34

23 (20%)

14 (21%)

9 (18%)

ceived TXA as a bolus in the operating room. Only 8 out of the 22 sub-

23 (46%)

TXA continued to receive it in hospital. Median time to receiving TXA was 1.8 h (IQR 1.05-3 h),

Penetrating 39 (33%) 22 (33%) 17 (34%) Glasgow Coma Score on initial presentation

Mean (SD)

1.2 (1.1)

1.3 (1.2)

1.2 (1.1)

<=1

69 (59%)

38 (57%)

31 (62%)

N1-<=3

40 (34%)

26 (39%)

14 (28%)

N3

8 (7%)

3 (4%)

5 (10%)

type of injury

Blunt

78 (67%)

45 (67%)

33 (66%)

Mean (SD)

11 (4.6)

11 (4.6)

12 (4.6)

Severe (3-8)

32 (27%)

20 (30%)

12 (24%)

Moderate (9-12)

14 (12%)

10 (15%)

4 (8%)

Mild (13-15)

67 (57%)

33 (49%)

34 (68%)

Not known

4 (3%)

4 (6%)

0 (0%)

Table 2

Primary outcomes (N = 4328a).

35-44

21 (18%)

15 (22%)

6 (12%) jects that received a pre-hospital dose of

N44

51 (44%)

28 (42%)

Time since injury to ER presentation (hours) and 76% of patients received it within 3 h.

n %b

Systolic blood pressure on initial presentation

Indication for tranexamic acid

117

Any tranexamic acid

67

57.3

Pre-hospital

22

18.8

In-hospital

52

44.4

Pre- and in-hospital

8

6.8

Bolus as per CRASH

55

47.0

Any bolus

64

54.7

Infusion as per CRASH

15

12.8

Any infusion

23

19.7

Mean (SD)

97 (41)

88 (42)

109 (38)

CRASH bolus and infusion

10

8.5

<=75 mm Hg

33 (28%)

22 (33%)

11 (22%)

Any bolus and infusion

17

14.5

76-89 mm Hg 21 (18%) 12 (18%)

9 (18%)

>=90 mm Hg 63 (54%) 33 (49%)

30 (60%)

Timing of tranexamic acid administration

n %c

Heart rate on initial presentation

Received tranexamic acid

67

Mean (SD) 112 (35) 108 (40)

117 (28)

Mean time in hours (standard deviation)

3.2 (6.0)

b77 bpm 16 (14%) 13 (19%)

77-91 bpm 8 (7%) 4 (6%)

3 (6%)

4 (8%)

Median time in hours (interquartile range)

<=1 h

1.8 (1.05-3)

16 23.9

92-107 bpm 9 (8%) 5 (7%)

4 (8%)

N1 to 3 h

35 52.2

N107 bpm 84 (72%) 45 (67%)

39 (78%)

N3 h

N8 h

16 23.9

3 4.5

ISS a N refers to number of subjects that presented to Royal Columbian Hospital emergency

department for trauma between April 2012 to June 2015.

Mean (SD)

26 (16)

27 (16)

25 (16)

Mild (b9)

2 (2%)

0 (0%)

2 (4%)

Moderate (9-15)

25 (21%)

11 (16%)

14 (28%)

Severe (16-25)

36 (31%)

23 (34%)

13 (26%)

Profound (N25)

54 (46%)

33 (49%)

21 (42%)

b Percentage of the 117 subjects that met indication for tranexamic acid, that received each category of dosing.

c Percentage of the 67 subjects that received any form of tranexamic acid, that received it within each time frame.

Table 3

Secondary outcomes during first 28 days of hospital stay.

Overall (n = 117)

Tranexamic acid (n = 67)

No tranexamic acid (n = 50)

?2

In-hospital mortality at 28 days

22 (19%)

14 (21%)

8 (16%)

p = 0.5

Blood transfusions

104 (89%)

61 (91%)

43 (85%)

p = 0.4

Thromboembolic events

8 (7%)

4 (6%)

4 (8%)

p = 0.7

Surgery

85 (73%)

52 (78%)

33 (66%)

p = 0.2

Table 4

Blood transfusions received during first 28 days of hospital stay.

PRBC (units)

Tranexamic acid

No tranexamic acid

Overall

Median

8

4

6

Mean (SD)

14 (17)

7 (11)

11 (15)

PRBC — packed red blood cells.

Odds ratio for mortality was not statistically significant different be- tween TXA and no-TXA groups. Odds ratio given TXA exposure was 1.39 (0.53-3.62). Odds ratio given drug administration <=3 h (vs N3 h) was

5.13 (0.62-42.75). Most patients received blood transfusions in addition to surgical interventions (Tables 3 and 4). Common surgeries were lap- arotomies and/or orthopedic in nature (Table 5). There were 8 throm- boembolic events, 4 in each group. There were 3 episodes of deep vein thrombosis and 1 Internal carotid artery thrombus in the TXA group, and 2 Pulmonary embolisms and 2 episodes of deep vein thrombosis in the no-TXA group.

Secondary outcomes of in-hospital mortality, blood transfusions, vascular occlusions, and surgical interventions were not statistically dif- ferent between the two groups (Table 3). This study was not powered to detect differences in these outcomes, however the data was analyzed for descriptive purposes.

  1. Discussion

The results demonstrate that more than half of adult trauma patients meeting the indication for TXA received the medication. However, b10% received it according to the CRASH-2 protocol. Of those that received any regimen of TXA, 76% did so within 3 h of presentation to the emergency department.

Reasons for alternate TXA regimens were not recorded in health re- cords. One possible reason could be a change in clinical status. Perhaps patients initially suspected to be bleeding were later found not to be, or those that were hemodynamically unstable then stabilized. Another reason could be discontinuity in care. It was observed that several times, a bolus was given pre-hospital, but the infusion was not given in-hospital. Alternatively, a bolus was given in the emergency depart- ment and patients were subsequently transferred to a different service (i.e. surgery, ICU etc.) where therapy was not continued. Similarly, some infusions were started in one unit, and not continued after trans- fer to another ward. Another possibility is lack of familiarity among

Table 5

Types of surgical interventions during first 28 days of hospital stay. Types of surgical interventions

Total

TXAa

No TXA

Neuro

7

5

2

Laparotomy

56

42

14

Orthopedic

66

40

26

Thoracic

19

13

6

Plastics

19

11

8

Vascular

14

9

5

Other

20

9

11

Total

201

129

72

a Tranexamic acid group.

health care providers with the indication and dosing protocol for TXA in the trauma setting. As noted previously, TXA is used in various set- tings to prevent hemorrhage and perhaps providers were using dosing established in other situations.

Use of TXA experienced initial interest after CRASH-2. However, there has been considerable controversy and critique surrounding its use since the CRASH-2 results were published. One of the critiques is that fibrinolytic activity was not measured, so exact mechanism of TXA in trauma cannot be certain [11, 14]. Moreover, there was no differ- ence in Transfusion requirements between groups, although increased survival may have led to more opportunity to receive transfusions [11, 14]. Most patients in CRASH-2 were in low and middle-income coun- tries, and b2% of patients had rapid access to blood products, surgery, and advanced critical care [9, 14]. The role of TXA in high-income coun- tries with faster transportation times, easier access to diagnostic imag- ing and critical care services, and where protocols normally include fresh-frozen plasma with endogenous antifibrinolytics, is less clearly known [14]. CRASH-2 has also been criticized for limited adverse events reporting, and other unreported data [15]. These concerns, as well as non-randomized controlled trials that later found an increase in venous thromboembolism, have perhaps led to a more tailored role in trauma, restricted to those in severe shock [15]. Two randomized trials, PATCH (Pre-hospital Antifibrinolytics for Traumatic Coagulopathy and Haem- orrhage) and STAAMP (Study of Tranexamic Acid During Air Medical Prehospital transport Trial) are currently underway in Australia and New Zealand, and the United States, respectively [16, 17].

It is difficult to conclude whether the use of alternate regimens was due to clinical status, lack of continuity in care during transfers, lack of familiarity among providers or uncertainty of benefit. However, the main concern around incomplete regimens (i.e. bolus-only, shorter in- fusions etc.) is that the main evidence that supports the use of TXA in trauma is CRASH-2, where all patients included in that study received a bolus as well as an infusion [11]. The use of alternate regimens may not confer the same mortality benefit as previously demonstrated. An- other important observation is only 76% of subjects received the drug within 3 h. This is important because post-hoc analyses of CRASH-2 have shown benefit of TXA only when given within 3 h, while there was actually an increase in hemorrhagic death if given in greater than that time period [12].

Our findings showed no difference in mortality with TXA exposure. CRASH-2 required over 20,000 patients to find a 1.5% absolute risk re- duction in mortality, therefore we did not expect this retrospective study of 117 patients to find a statistical difference [11]. Furthermore, because of the non-randomized nature of our study, we cannot make any strong conclusions about mortality given the presence of confound- ing. It is likely that patients that received TXA earlier in their hospital course had more severe trauma and were at higher risk of mortality. This was supported in our data with the lower GCS scores, more trans- fusions, and more surgical interventions in the TXAgroup; although these differences did not reach statistical significance. CRASH-2 similarly did not find a difference between groups in blood transfusions, throm- boembolic events, and surgeries [11]. We pre-specified an analysis of these endpoints for exploratory descriptive purposes only.

We attempted to compare our results to the available literature. It is immediately noticeable that the accrual rate for our study was quite low (2.7%). This is likely due to the use of the BCTR, which also includes asphyxial, thermal, and minor traumas (i.e. falls), giving 4328 patients

Declaration of interest“>as the total number of trauma admissions in the examined time period. As other studies of TXA have not reported accrual rate, it is difficult to make comparisons [12, 18]. Our baseline demographics were similar to CRASH-2., where patients were mainly young, male, and suffered blunt trauma [11]. The majority presented with systolic blood pressure over 90 mm Hg, and about 50% had an initial heart rate N 107 bpm. Ini- tial GCS was mild (13-15) for 68% [11]. The mean time to presentation in our study was 1.2 h versus 2.8 h in CRASH-2. This could be explained by the fact that most centers in CRASH-2 were in less developed coun- tries with possibly more barriers to accessing health care. However, we conclude that our patients could have been included in CRASH-2, and perhaps would have received the same benefits TXA.

Our secondary outcomes appear to correlate with previous popula-

tion data. The mortality rate of 19% was similar to CRASH-2 (15%) [11]. Patients at our study center received more blood transfusions and surgi- cal interventions, likely due to more ready access to these resources. While vascular occlusions have long been a hypothetical risk with TXA, our results seem to correlate with other studies that have shown that this threat is not real [9].

Our study is one of the few assessing the use of TXA in trauma pa- tients in a tertiary center in the post-CRASH-2 era. TXA has been inte- grated into hospital and prehospital ambulance services in several countries, including Canada [19, 20]. Yet, one study of its use as part of a massive transfusion protocol at an American tertiary center revealed that 38% of eligible trauma patients received the drug [21]. Other studies have examined the benefits of this drug in vastly different settings such as combat [18, 22].

There are limitations to our study. Firstly, due to its retrospective de- sign, we were restricted to data available in hospital records, which proved difficult in assessing the significance of hemorrhage during screening. CRASH-2 did not publish their definition of “significant hem- orrhage”, nor provide guidance on how patients were assessed for inclu- sion in regards to bleeding. Subjects were included based on the “uncertainty principle”, meaning that those for which the clinician was “substantially uncertain” as to the appropriateness of an antifibrinolytic were included and randomized, while those in which it was “reasonably certain” that an antifibrinolytic was either indicated or contra-indicated were not included [11]. Other studies included pa- tients based on whether they received blood transfusions [18]. Based on this information, we felt it was appropriate to include patients in which hemorrhage leading to hemodynamic instability was docu- mented, or in which they received blood transfusions immediately after admission for hemorrhage, and a more reasonable indication for its administration was not apparent. We did not include those “at risk of significant hemorrhage” due to the difficulty in assessing this retro- spectively, and therefore we may not have captured the true CRASH-2 population. It is possible that if those “at risk” had also been included, the rate of appropriate drug usage may have been even lower than our results demonstrated. Moreover, TXA is commonly used as a bolus in the operating room. Many trauma patients underwent surgeries dur- ing their hospital stay, with 8 subjects receiving the drug in the operat- ing room. Whether it was administered for trauma or a peri-operative procedure is not known, and therefore is a definite confounder.

Results of this retrospective analysis have identified care gaps and have implications for future studies. Next steps would be to identify rea- sons that trauma patients are not receiving TXA, as well as the rationale behind use of alternate dosing regimens. This information can be used for quality improvement initiatives in trauma care, such as revision of pre-printed orders, educational workshops for health professionals and/or quality improvement cycles, both at Royal Columbian Hospital, as well as at other trauma centers in Canada.

  1. Conclusions

Less than 10% of presenting adult trauma patients that met indica- tion for tranexamic acid at a tertiary care center received it according

to the CRASH-2 protocol. Of those patients that received tranexamic acid in any form, 76% did so within the recommended 3 h. The results have identified areas for further inquiry to elucidate reasons trauma pa- tients are not receiving tranexamic acid, as well as possible quality im- provement initiatives in trauma care centers in Canada.

Acknowledgements

Authors would like to acknowledge Flora Young, Kathleen Fyvie, Joe Haegert and Iain MacPhail for their assistance during the course of this study.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Declaration of interest

None.

Appendix A. Tranexamic acid-supplemental information

Other cautions/contraindications [23]

  • History or risk thrombosis
  • Acquired colour vision disturbances
  • Active arterial/Venous thromboembolic disease (deep vein thrombo- sis, pulmonary embolism, cerebral thrombosis)
  • Subarachnoid hemorrhage (reduced risk for re-bleed offset by in- crease in cerebral ischaemia)
  • Haematuria: can lead to development of clots in ureters; few reports of acute renal cortical necrosis with oliguria, and renal failure
  • Oral contraceptive use
  • Other adverse events [23]
  • Dose-related Gastrointestinal symptoms
  • Hypotension and dizzy
  • Ocular/Visual disturbances
  • Hypersensitivity
  • Skin
  • MSK pain
  • Convulsions
  • Cautions and contraindications listed above are as per available in- formation on tranexamic acid use, and do not reflect the exclusion criteria for this study.

    Appendix B. Inclusion/exclusion additional information

    CRASH-2 also had a clinical inclusion criterion: Included those considered “at risk of significant hemorrhage”.

    E.g. compensated hemorrhage and stable vital signs bleeding stopped but might recommence following volume resuscitation [11].

    This clinical inclusion criterion is not included in this study, as the retrospective nature of our research would make this difficult to assess, and possibly confounded. By doing this, we may be excluding patients that may have benefitted from tranexamic acid treatment in our assess- ment of the outcomes.

    CRASH-2 also excluded those with a history of cardiovascular dis- ease, thromboembolic events, bleeding diathesis, renal failure with Cr N 250micromol/L, or those that were pregnant or on anticoagulants [11].

    References

    1. WHO, Injuries and violence: the facts [Internet]. WHO. [cited 2017 Oct 9]. Available from: http://www.who.int/violence_injury_prevention/key_facts/en/
    2. Years of Potential Life Lost (YPLL) 1981-2015 [Internet]. National Center for Injury Prevention and Control; 2017 Available from: https://www.cdc.gov/injury/ wisqars/fatal.html.
    3. Evans JA, van Wessem KJP, McDougall D, Lee KA, Lyons T, Balogh ZJ. Epidemiology of traumatic deaths: comprehensive population-based assessment. World J Surg 2010 Jan;34(1):158-63.
    4. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute coagu- lopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008 May;64(5):1211-7 (discussion 1217).
    5. Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma 2008 Oct;65(4):748-54.
    6. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, iden- tification and effect. Curr Opin Crit Care 2007 Dec;13(6):680-5.
    7. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indica- tions. Drugs 1999 Jun;57(6):1005-32.
    8. WHO. 19th WHO model list of essential medicines [Internet]. [cited 2015 Jul 2]. Available from: http://www.who.int/selection_medicines/committees/expert/20/ EML_2015_FINAL_amended_JUN2015.pdf; 2015.
    9. Tengborn L, Blomback M, Berntorp E. Tranexamic acid–an old drug still going strong and making a revival. Thromb Res 2015 Feb;135(2):231-42.
    10. Lexi-drugs [Internet]. Lexicomp online. [cited 2018 May 28]. Available from: http:// www.wolterskluwercdi.com/lexicomp-online/.
    11. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, et al, with CRASH-2 trial collaborators. 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 Lond Engl 2010 Jul 3;376(9734): 23-32.
    12. Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, et al, with CRASH-2 collab- orators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet Lond Engl 2011 Mar 26;377(9771):1096-101 (1101.e1-2).
    13. Palmer C. Major trauma and the injury severity score — where should we set the bar? Annu Proc Assoc Adv Automot Med 2007;51:13-29.
    14. Gruen RL, Mitra B. Tranexamic acid for trauma. Lancet Lond Engl 2011 Mar 26;377 (9771):1052-4.
    15. Walsh M, Thomas S, Moore E, Moore H, Piscoya A, Hake D, et al. Tranexamic acid for trauma resuscitation in the United States of America. Semin Thromb Hemost 2017 Mar;43(02):213-23.
    16. Mitra B, Mazur S, Cameron PA, Bernard S, Burns B, Smith A, et al. PATCH-trauma study investigators. Tranexamic acid for trauma: filling the “GAP” in evidence. Emerg Med Australas EMA 2014 Apr;26(2):194-7.
    17. Brown JB, Neal MD, Guyette FX, Peitzman AB, Billiar TR, Zuckerbraun BS, et al. Design of the Study of Tranexamic Acid during Air Medical Prehospital Transport (STAAMP) trial: addressing the knowledge gaps. Prehospital Emerg Care Off J Natl Assoc EMS Physicians Natl Assoc State EMS Dir 2015 Mar;19(1):79-86.
    18. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg Chic Ill 1960 2012 Feb;147(2):113-9.
    19. Vu EN, Schlamp RS, Wand RT, Kleine-Deters GA, Vu MP, Tallon JM. Prehospital use of tranexamic acid for hemorrhagic shock in primary and secondary air medical evac- uation. Air Med J 2013 Oct;32(5):289-92.
    20. Ausset S, Glassberg E, Nadler R, Sunde G, Cap AP, Hoffmann C, et al. Tranexamic acid as part of remote damage-control resuscitation in the prehospital setting: a critical appraisal of the medical literature and available alternatives. J Trauma Acute Care Surg 2015 Jun;78(6 Suppl 1):S70-5.
    21. Farrell NM, Wing HA, Burke PA, Huiras P. Addition of tranexamic acid to a traumatic injury massive transfusion protocol. Am J Health-Syst Pharm AJHP Off J Am Soc Health-Syst Pharm 2015 Jun 15;72(12):1059-64.
    22. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association 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.
    23. Tranexamic acid. Martindale: the complete drug reference [Internet]. Online. The Pharmaceutical Press; 2013 [cited 2015 Jul 2]. Available from: https://www- medicinescomplete-com.ezproxy.library.ubc.ca/mc/martindale/current/1726-j. htm?q=tranexamic%20acid&t=search&ss=text&p=1#_hit.

    Leave a Reply

    Your email address will not be published. Required fields are marked *