a b s t r a c t

Objective: antifibrinolytic agent Tranexamic acid has a potential clinical benefit for in-hospital patients with severe bleeding but its effectiveness in pre-hospital settings remains unclear. We conducted a systematic review and meta-analysis to evaluate whether pre-hospital administration of TXA compared to placebo improve patients’ outcomes?

Methods: PubMed, MEDLINE, Cochrane Library, WHO International Clinical Trials Registry Platform, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, clinicaltrials.gov and Google Scholar databases were searched for a retrospective, prospective and randomized (RCT) or quasi-RCT studies that assessed the effect of prehospital administration of TXA versus placebo on the outcomes of trauma patients with significant hemor- rhage. The main outcomes of interest were 24 hour 30-day mortality and in-hospital thromboembolic complica- tions. Two authors independently abstracted the data using a data collection form. Results from different studies were pooled for the analysis, when appropriate.

Results: Out of 92 references identified through the search, two analytical studies met the inclusion criteria. The effect of TXA on 24-hour mortality had a pooled odds ratio (OR) of 0.49 (95% CI 0.28-0.85), 30-day mortality OR of 0.86 (95% CI, 0.56-1.32), and Thromboembolic events OR of 0.74 (95% CI, 0.27-2.07).

Conclusion: Prehospital TXA appears to reduce early mortality in trauma patients. The Pooled analysis also shows a trend toward lower 30-day mortality and reduced risk of thromboembolic events. Additional randomized con- trolled clinical trials are needed to determine the significance of these trends.

(C) 2018

1. Introduction

According to the World Health Organization, trauma accounted for 9% of the global mortality and is considered as a serious Public health concern worldwide [1]. Scientific evidence reported traumatic bleeding to be the leading cause of early mortality in injured patients [2-5]. Around 25% of the trauma patients developed acute coagulopathy as

* Corresponding author at: Department of Surgery, Trauma Surgery, Clinical Research, Hamad General Hospital, P.O. Box 3050, Doha, Qatar.

E-mail addresses: [email protected] (A. El-Menyar), [email protected] (B. Sathian), [email protected] (M. Asim), [email protected] (R. Latifi).

complication and up to 40% of them died secondary to hemorrhagic shock [5-9]. Recent researches demonstrated that early treatment of acute coagulopathies and hemorrhagic shock considerably minimizes post traumatic deaths [6,10]. Suspected non-compressible bleeding that leads to hemodynamic instability should be managed through fluid resuscitation, permissive hypotension, administration of tranexamic acid, and rapid transport to the nearest suitable center [11]. tranexamic acid is cost effective antifibrinolytic agent and its early (within 3 h post injury) in-hospital administration in patients with trauma- induced hemorrhagic shock showed significant reduction in mortality and thromboembolic events [12-14]. By effectively controlling bleeding at early stage post trauma, TXA has the potential to prevent the subse- quent hypoxia and acidosis that complicate severe bleeding. Based on two large studies, it appears that TXA shows time-dependent effect and

https://doi.org/10.1016/j.ajem.2018.03.033

0735-6757/(C) 2018

methodological quality“>potential benefit in the treatment of hemorrhagic shock in the civilian and military populations [12,15]. However, these earlier studies primarily focused on the in-hospital use of TXA in trauma patients.

Currently, European guidelines for management of major bleed- ing and coagulopathy following trauma, recommended early admin- istration of TXA to prevent bleeding [16]. To date, the evidence of prehospital TXA use in trauma patient is debatable due to lacking of published randomized control studies. Herein, we conducted a systematic review and meta-analysis as the first update on the cur- rent evidence regarding the efficacy of the Prehospital use of TXA in trauma patients.

Objective

The objective of this study is pooling of effects of prehospital TXA ad- ministration on the mortality at 24 h and 30 days, and to evaluate the risk of developing thromboembolic complications during the hospital course in civilian population.

1. Methods

This systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) Statement. The study was registered at the Inter- national prospective register of systematic reviews (PROSPERO n. CRD42017077517).

Literature searches

A systematic review was carried out using PubMed, MEDLINE, Cochrane Library, WHO International Clinical Trials Registry Platform, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and clinicaltrials.gov and Google scholar electronic databases. We used the keywords “Tranexamic Acid”; “prehospital setting”; “point of injury”; “trauma” [in Title/Abstract]. The medical subject headings (MeSH) terms used were prehospital [All Fields] AND (“tranexamic acid” [MeSH Terms] OR (“tranexamic” [All Fields] AND “acid” [All Fields]) OR “tranexamic acid” [All Fields]) AND (“injuries” [Subheading] OR “in- juries” [All Fields] OR “trauma” [All Fields] OR “wounds and injuries” [MeSH Terms] OR (“wounds” [All Fields] AND “injuries” [All Fields]) Inclusion/exclusion criteria“>OR “wounds and injuries” [All Fields]). Additional searches were con- ducted using reference lists of studies and review articles for a selection of relevant articles.

Inclusion/exclusion criteria

The inclusion criteria were (1) original studies, (2) English lan- guage, (3) published in the period from 01 January 2000 through 31st August 2017 (4) assessed “Tranexamic Acid” or “prehospital” and “traumatic injury” (5) patient population (6) patients of any age, gender, and ethnicity. Articles other than original studies such as case reports, reviews, letters to the editor and commentaries were excluded. Literatures that did not include comparisons or out- comes were also excluded.

The consensus on inclusion/exclusion criteria was reached based on the fact that whether the study provides information about the efficacy of TXA [mortality at 24 h and 30 days, and thromboembolic complica- tions] in prehospital setup in patients’ sustained traumatic injury. Therefore, even studies with smaller sample sizes were also included in the initial evaluation.

Definitions

Participants: traumatic injury patients presenting to the ED requiring blood transfusions.

Intervention: pre hospital tranexamic acid administration at any dose and route after trauma.

Control: placebo administration.

Outcomes: 24 hour mortality, 30 day mortality, and thromboembolic events.

We considered any plausible definitions used by original articles.

Thromboembolic complications: symptomatic thromboembolic com- plications are diagnosed when patients showed significant clinical signs or symptoms/radiological evidence of deep venous thrombosis or pulmonary embolism.

Data extraction

The titles of the research articles obtained from the initial data- base searches were screened and relevant papers were selected. Then the abstracts and full texts were reviewed according to the in- clusion criteria for final selection. The titles, abstracts, and full-text articles were reviewed independently by two researchers (AE & BS). Agreement between the authors on the quality of the articles ranged between 90 and 100%. All the disagreements were resolved by consensus among the authors. Extracted data included authors, the origin of studies, source population, study settings and dura- tion, inclusion/exclusion criteria, data sources and measurement, sample size, thromboembolic complications and mortality at 24 h and 30-days.

Methodological quality

We used “Grading quality of evidence and strength of recommen- dations” (GRADE criteria) to assess the quality of the included stud- ies and rate the Level of evidence. The methodological quality of the selected studies was assessed based on certainty assessment [Study design, Risk of bias, Inconsistency, Indirectness, Imprecision, and Other considerations] by Cochrane Grade pro software. We have evaluated the quality of the proposed outcomes i.e. thromboembolic complications and mortality at 24 h and 30-days.

Data analysis and synthesis

Odds ratios (OR) were calculated for categorical variables.

The decision to select either fixed effect or random effects model depends on results of statistical tests for heterogeneity. Data hetero- geneity was assessed using the Cochrane Q homogeneity test with significance set at p b 0.10. If the studies were statistically homoge- neous, fixed effect model was selected. A random effects model was used when studies were statistically heterogeneous. The I² test is the ratio of true heterogeneity to the total variation in observed ef- fects. A rough guide to interpretation of I² test is 0 to 25%: might not be important; 25 to 50%: may represent moderate heterogeneity; 50 to 75%: may represent substantial heterogeneity; and N75%: consid- erable heterogeneity.

Pooled estimates of mortality were calculated using a Microsoft Excel add-in, MetaXL v. 5.3 (EpiGear International Pty Ltd, Sunrise Beach, Queensland, Australia). GRADEpro GDT was used for studies grading.

1. Results

The search produced a total of 92 articles; 75 article were either non relevant to the topic, duplicates or review articles which were excluded initially. The relevant titles and/or abstracts and full text

of the 17 articles underwent detailed evaluation; of which 7 articles were further eliminated which were mainly based on protocol devel- opment and narrative reviews and the remaining 10 articles studies [17-24] were reviewed further. Among them 8 studies [19-24] were excluded as per the criteria for meta-analysis [mortality at 24 h and 30 days, and thromboembolic complications] and availability of only abstracts. Among the 8 excluded studies 7 [8,19-22,24] did not have controls and did not assess the outcome measures. One study had controls but did not have outcome measures [23]. Finally, two original studies met all the review criteria and were considered for the final meta-analysis (Fig. 1, Table 1). Both the studies lasted for 3 years. The total number of patients pooled was 769, of which 386 were in TXA group and 383 in control group. The first study [18] was a retrospective analysis, in which a cohort of patients who re- ceived prehospital TXA was compared to a propensity score-based matched control. TXA was provided by 20 of the 35 air rescue heli- copters during the 3-year study period. Early mortality was signifi- cantly lower in the TXA cohort (5.8% vs 12.4%). However, the overall in-hospital mortality was comparable among the two groups (p = 0.72). The mean time to death was significantly longer in TXA group (8.8 vs 3.6 days). No significant differences were observed be- tween the intervention and control groups in terms of the thrombo- embolic events.

In the second study, 253 trauma patients were prospectively recruit- ed [17]. Although, it was not statistically significant, the prehospital in- tervention group trended toward a lower 24-h (p = 0.25), 48-h (p = 0.76), and 28-day mortality rates (p = 0.23). Furthermore, a reduction in the total number of blood products was observed following the ad- ministration of TXA (p = 0.01).

Table 2 shows details of the quality assessment based on GRADE criteria of the two selected studies. Both studies were of moderate qual- ity. Table 3 & Supplementary file demonstrate the quality assessment of the included studies which shows the moderate level of evidence based on the GRADE criteria.

Outcome measures

1. Effect of TXA on 24-hour mortality

Only 2 prehospital TXA studies compared the 24-hour mortality in the TXA group with a control group. Total of 61 patients died within 24 h of injury [20 in TXA group and 41 in placebo group] and a post hoc statistical power of 93%. Therefore, we considered these studies for the meta- analysis (Fig. 2). The pooled result manifested a statistically significant re- duction in 24-hour mortality in the intervention group compared to the control group (OR 0.49; 95% CI, 0.27 to 0.84).

Fig. 1. Flow diagram of study Selection process for systematic review.

Table 1

Summary and assessment of the eligible studies for the current meta-analysis.

Study Study design & duration

Sample size Inclusion criteria Findings Conclusion Limitations

Neeki et al. [17]

Wafaisade et al. [18]

Prospective (prehospital) Civilian 2014-2016

Retrospective (prehospital) Civilian January 2012 and December 2014

128 TXA administrated and 125 control matched based upon ISS, hemodynamic profiles, and mechanism of injury

258 TXA administrated

and 258 propensity matched controls

Criteria for the prehospital and hospital use of TXA:

• Blunt or penetrating trauma with signs and symptoms of hemorrhagic shock
• SBP b90 mm Hg at scene of injury, during air and/or ground medical transport, or upon arrival to designated trauma centers
• Any sustained blunt or penetrating injury b3 h
• Patients high risk for significant hemorrhage (estimated blood loss of 500 ml at scene accompanied with a heart rate N120; Uncontrolled bleeding by direct pressure or tourniquet, major amputation of any extremity above the wrists and above the ankles)

Patients were treated with TXA at the discretion of the emergency physician.

• Early mortality was significantly lower in the TXA group.
• Complications and overall hospital mortality was similar in both groups.
• Early mortality was significantly lower in the TXA group.
• Complications and overall hospital mortality was similar in both groups.

TXA was associated with prolonged time to death and significantly improved early survival

TXA was associated with prolonged time to death and significantly improved early survival

• Initial implementation of TXA administration between the prehospital and hospital groups did not occur simultaneously.
• The delayed onset of TXA administration in the prehospital group was due to the need for approval by local and state EMS regulatory authorities, as well as personnel training for administration in the prehospital setting.
• This study was limited by design. The prospective cohort design in comparison to a randomized control design did not allow us to administer TXA in a blinded fashion.
• Laboratory parameters

(e.g., D-dimers, thromboelastometry, interleukin-6) not available.

• Exact timing of prehospital TXA administration and dosages (TXA or fibrinogen) not documented.
  

  Effect of TXA on 30-day mortality

  We pooled the results from these two studies in Fig. 3. Total of 99 pa- tients died within 30 days of injury [44 in TXA group and 55 in Placebo group] and a post hoc statistical power of 23.6%. The pooled results indi- cated a trend of reduction for 30-day mortality in the intervention group with respect to the control group but it did not reach statistical signifi- cance (OR 0.86; 95% CI, 0.559 to 1.32).

  Effect of TXA on thromboembolic events

  Total of 18 patients developed thromboembolic events during hospi- tal stay [6 in TXA group and 12 in Placebo group] and a post hoc statis- tical power of 29.7%. The pooled result showed a non-significant trend of reduction in thromboembolic events in the intervention group as compared to the controls (OR 0.74; 95% CI, 0.267 to 2.066) (Fig. 4). Although the latter 2 outcomes were statistically not significant

  Table 2

  Quality assessment of the included studies in the meta-analysis.

  Criteria Neeki MM et al (Germany) [17] Wafaisade et al (Germany) [18]

  Study design Non-RCT.

  Prospective study (prehospital)

  Risk of bias Low or unclear risk of bias. Plausible bias unlikely to seriously alter the results.

  This study has no serious risk of bias, which does not downgrade the quality.

  Inconsistency No

  The study population was Civilian, Intervention was TXA vs No TXA, and Outcome assessment was consistent in terms of mortality (24 h and 30 days) and thromboembolic events.

  Indirectness There is no indirectness as all adult trauma patients with risk of bleeding were included, intervention was same dose of TXA, and comparator group was similar, outcome measure was appropriate to assess the effect of intervention.

  Imprecision There is possibility of imprecision because of wide confidence interval.

  One point imprecision may exists.

  24 Hour mortality [OR 0.54 (0.18, 1.66)]

  30 Day mortality [OR 0.87 (0.32, 2.32)]

  Thromboembolic events [OR 0.98 (0.14, 7.04)]

  Non-RCT.

  Retrospective study (prehospital)

  Low or unclear risk of bias. Plausible bias unlikely to seriously alter the results.

  This study has no serious risk of bias, which does not downgrade the quality. No

  The study population was Civilian, Intervention was TXA vs No TXA, and Outcome assessment was consistent in terms of mortality (24 h and 30 days) and thromboembolic events.

  There is no indirectness as all adult trauma patients with risk of bleeding were included, intervention was same dose of TXA, and comparator group was similar, outcome measure was appropriate to assess the effect of intervention.

  There is no possibility of imprecision. It does not appear to be an issue. 24 Hour mortality [OR 0.47 (0.25, 0.89)]

  30 Day mortality [OR 0.86 (0.53, 1.38)]

  Thromboembolic events [OR 0.67 (0.20, 2.22)]

  Other

  considerations

  There is no publication Bias, Large effect, dose response gradient. But anticipated plausible confounding factor might reduce demonstrated effect because it is a prospective non RCT. In addition, there may be publication bias because of less sample size.

  There is no publication Bias, Large effect, dose response gradient. But anticipated plausible confounding factor might reduce demonstrated effect because it is a retrospective non RCT.

  Quality of evidence

  Moderate Moderate

  Table 3

  Quality assessment of the eligible studies.

  Tranexamic acid vs. no tranexamic acid be used for pre hospital trauma patients

  	Patient or population: trauma patients Setting: prehospital Intervention: tranexamic acid Comparison: no tranexamic acid
  	Outcomes	Anticipated absolute	effectsa (95% CI)	Relative effect	No. of participants	Certainty of the evidence	Comments
  		Risk with no tranexamic acid	Risk with tranexamic acid	(95% CI)	(studies)	(GRADE)
  	Mortality assessed with time: 24 h	Low 72 per 1000	37 per 1000 (21 to	OR 0.49 (0.28 to 0.85)	386 cases 383 controls	???? MODERATE	CRITICAL
  			62)		(2 observational
  		High 124 per 1000	65 per 1000 (38 to		studies)
  	Mortality assessed with time: 30 days	Low	107)	OR 0.86 (0.56 to	386 cases	????	IMPORTANT
  		104 per 1000	91 per 1000 (61 to	1.32)	383 controls	MODERATE
  		High	133)		(2 observational studies)
  		163 per 1000	143 per 1000 (98 to
  	Thromboembolic events assessed with:	Low	204)	OR 0.74 (0.27 to	386 cases	????	IMPORTANT
  	time: 30 days	16 per 1000	12 per 1000 (4 to	2.07)	383 controls	MODERATE
  		High	33)		(2 observational studies)
  		39 per 1000	29 per 1000 (11 to 77)

  GRADE Working Group grades of evidence. High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

  ^a The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio.

  because of less statistical power, both might still have clinical implications.

  1. Discussion

  Although, there is no published randomized clinical trial (RCT) yet, at least 10 published studies have addressed the beneficial effect of prehospital TXA use for the treatment of significant bleeding in trauma

  patients [8,16-24]. Up to the best of our knowledge, this is the first attempt to conduct a meta-analysis in this regard. Literature searching and data analysis for the present meta-analysis resulted in two moderate-quality observational studies described the hypothesis that prehospital administration of TXA in civilian trauma patients would re- duce the risk of mortality and thromboembolic complications compared to placebo [17,18]. The first study was under-powered prospective study with wide confidence intervals, whereas the second study was

  Fig. 2. Forest plot representing the effect of tranexamic acid on 24-hour mortality.

  Fig. 3. Forest plot representing the effect of tranexamic acid on 30 day mortality.

  early use o”>retrospective and appropriately powered to measure the study out- comes [17,18].

  Our findings suggest that prehospital TXA administration could ef- fectively reduce early mortality with a trend of improved survival at 30-day post-traumatic injury. Although, the pooled results for the 30- day mortality did not get enough power to reach statistical significance, the results still have clinical implications. Furthermore, prehospital TXA did not increase the thromboembolic events in those who received TXA, compared to controls.

  TXA in emergency department (ED)

  Prior systematic reviews have shown that TXA is an effective peri- operative drug that minimizes the blood loss during elective surgery in trauma and non-trauma patients in the hospital settings [25-28]. The effect of TXA was shown to be time-dependent and better outcomes were observed for the hospital TXA administration within 3 h post inju- ry in polytrauma patients [8,10,16-19,21,22].

  There are 2 meta-analyses assessed TXA use in the ED [29,30]. Zehtabchi et al. conducted a meta-analysis of only two studies that eval- uated the in-hospital use of TXA in patients with traumatic brain injury [29]. These investigators showed the favorable effect of TXA on the overall mortality with a pooled relative risk of 0.64 which did not reach statistical significance. However, the risk of thromboembolic event was not accounted in the study outcome. The other meta- analysis quantified the efficacy of TXA use in reducing the risk of bleed- ing and thromboembolic events in patients undergoing orthopedic trauma surgery [30]. There was no significant difference in the risk of thromboembolic events (OR 0.97; p = 0.68) between the TXA and con- trol groups.

  TXA in CRASH-2 and its sub-analysis

  In the CRASH-2 study, the 28 day mortality rate was significantly re- duced with TXA use in the ED (14.5% in TXA group vs 16.0% in placebo group) with a relative risk of 0.91 (p = 0.003) [12]. In a sub-analysis of this study, Roberts et al. showed that, after giving TXA in the ED, the risk ratio of mortality was 0.68 (TXA given within the first h) and 0.79 (TXA given within the second or third h) [14]. Therefore, it is worth to further investigate how early the administration of TXA in trauma patient could be.

  Pre-hospital TXA in the contemporary literature

  A recent narrative review by Pinto et al [31] evaluated two articles which studied prehospital TXA use in a pooled sample of 53 trauma pa- tients [19,21]. The authors suggested that, based on the available litera- ture, it could be safe to use TXA in the prehospital settings. The review identified single observational study which aimed to assess the occur- rence of thromboembolic events related to TXA use in trauma patients.

  Similar to our findings, no significant difference was observed in that study for thromboembolic events in patients receiving TXA versus con- trols [32]. Thus, the accumulated evidence to date points to the safety of treatment with TXA; however, there is still need for further RCTs de- signed to evaluate the safety and efficacy of prehospital TXA use in trau- ma patients in terms of complications and mortality. We do believe that inclusion of findings from the ongoing clinical trials for prehospital TXA administration can yield sufficient power to get a statistical significance in the near future [29,30,33].

  Pre-hospital TXA in meta-analysis and clinical trials

  There is no prior meta-analysis addressed the TXA use in the prehospital settings so far, however, there are 3 ongoing clinical trials to investigate the safety and efficacy of prehospital TXA use in trauma patients [33-35]. Recently, few investigators have evaluated the use of prehospital TXA in trauma patients’ in civilian and military settings and had shown the feasibility of its use in the field [11,20,23]. However, there is a lack of high level of evidence based on clinical trials with suf- ficient statistical power to determine the safety and efficacy of prehospital TXA use.

  Recommendations for the early use of TXA

  Recently, the Department of Defense Committee on Tactil Combat Casualty Care (CoTCCC) supported the TXA use within the first 3 h post-injury at the prehospital settings if the there is a need for signifi- cant blood transfusion (shock, >=1 amputations, penetrating Abdominal injury or severe bleeding) [36]. Furthermore, there is a recommendation that the use of TXA under these settings should be preceded by the Thromboelastography evidence of hyperfibrinolysis (i.e., percent lysis at 30 min N3%) according to the Denver experience [37]. However, TEG may not be feasible in the EMS settings and in most of ED and if pre- sents, a trained staff should be there to avoid the delay of treatment. Also, occult hyperfibrinolysis in trauma may not be easily detected by viscoelastic studies including TEG [38]. A recent prospective, multicen- ter study assessed the coagulation profiles in 70 trauma patients receiv- ing TXA on-scene vs 38 historic control patients who did not receive TXA.

  The investigators used ROTEM for clotting assay at the scene and ED and found that the production of fibrinogen fragments was significantly lower in the TXA group. The authors concluded that early prehospital administration of TXA leads to clot stabilization and a reduction of fibri- nolytic activity, however, the study had a limitation of having a small sample size [39]. Few trauma centers have advocated or recommended the integration of TXA protocol in their prehospital phase by EMS in an attempt to provide an adjunct to early Hemorrhage control [Table 4] [40,41].

  As the contemporary literature is in favor of giving TXA as early as possible as the mortality and thromboembolic events are fewer

  Fig. 4. Forest plot representing the effect of tranexamic acid on thromboembolic events.

  compared to the controls, our findings would have implications for the clinical care of trauma patients particularly in the prehospital settings.

  Limitations

  The searches for this review were in most of the citation databases and reference lists from included studies. We have accessed the paid ar- ticles as well. Some limitations exist in the current study meta- analysis of the evidence. Our study included only the published stud- ies and the information of ongoing clinical trials. We could not find out the gray literature that is not published and so we admit the po- tential publication bias. We had only two studies and one of them did not have sufficient power and reported 28-day mortality. The total number of patients that received TXA was under 400. One study was prospective, but the other one was retrospective. Neither was randomized trial. Comparison groups were propensity matched or historical. Also, the information about transfusion volumes, the exact timing of prehospital TXA administration and dosages were missing, the cause of death was not documented, therefore deaths occurred due to hemorrhage or TBI are unknown, cannot determine whether TXA was associated with reduced mortality due to hemor- rhage. While this fact limits the generalizability of the findings, the quality of the included studies and absence of significant heteroge- neity validates the present analysis. We included only civilian inju- ries in the analysis. The inclusion of only 2 studies in this meta- analysis could be one of the limitations, however, we have done a

  post hoc Power calculation for 24 h mortality comparison, there were 41 mortality out of 383 in control group and 20 out of 386 in in- tervention group which showed a power of 92.62 at 5% significance level. Furthermore, Valentine et al., in their review, tried to answer about how many studies do we need to do a meta-analysis? and they showed that, given the need for a conclusion, the answer was “two studies,” because all other synthesis techniques are less trans- parent and/or are less likely to be valid [42].

  1. Conclusions

  In conclusion, prehospital TXA significantly reduces early mortal- ity in trauma patients. The pooled analysis also indicated lower 30- day mortality and reduced risk of thromboembolic events with the prehospital TXA use in trauma patients. Although the latter two out- comes were statistically not significant, both might still have clinical implications. Furthermore, high-quality randomized controlled tri- als are needed to support the routine use of prehospital TXA in major trauma patients. Although there are no enough eligible studies yet, the results of our attempt can be taken cautiously in consider- ation until proven otherwise. This information will substantiate the proposed beneficial effect of TXA administration for prehospital pro- tocol development.

  Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2018.03.033.

  Table 4

  Q&A for prehospital administration of tranexamic acid.

  Question & problem Comment & recommendation

  Bleeding trauma patients did not present within the timeframe allowed for safe and effective use of TXA in most of cases.

  The keys to survival remain the prompt hemorrhage control and rapid transport to a trauma center in the bleeding patient.

  TXA may be more effective on a population basis if incorporated into prehospital protocols

  • Prehospital TXA use should never replace field Bleeding control techniques, rapid transport to a trauma center, or the administration of blood or plasma.
  • TXA administration should never delay transport

  TXA use includes a bolus dose followed by an infusion over 8 h. Prior to the implementation of field TXA, the EMS agency and the receiving trauma

  center should jointly develop protocols to ensure eligible patients receive the appropriate bolus dose in the field and infusion dose at the hospital

  -Hand-over confusion and dose missing or duplication may occur

  -Repeat bolus doses of TXA should be avoided

  Limited evidence suggests that more venous thromboembolic events may occur when TXA is given to patients not requiring massive transfusion

  Compressible bleeding should be managed with pressure dressings, hemostatic agents, wound packing, or tourniquets.

  • A clear hand-off care report given by EMS providers is essential step,
  • Endorsement should states that TXA bolus has been given during transport to avoid repeat bolus doses and to ensure that infusion is initiated in a timely fashion.
  • Prehospital TXA administration should be clearly communicated with the next receiving provider. Simple adjuncts, such as stickers or wristbands applied to patients, may be used to aid in the information transfer
    • • • Indications should be based on evidence consistent with non-compressible hemorrhage in terms of penetrating thorax or abdominal trauma or unstable pelvis fractures along with heart rate N120 bpm and systolic blood pressure b90 mm Hg
        • Vital sign may be adjusted for Geriatric population

  Prehospital TXA should be administered only to patients with non-compressible bleeding.

  Definitive surgical control at a trauma center is need. Patients receiving prehospital TXA should be transported to a Level I or II trauma center

  if available.

  If geographic or other factors preclude direct trauma center transport The first receiving hospital should be capable of continuing the TXA infusion and

  implementing hemorrhage-control procedures

  Administration should be reviewed and protocols constantly refined to avoid unnecessary or incomplete doses, inappropriate patient selection, or lack of infusion following the initial bolus.

  • • • • • Prehospital TXA use should be monitored closely in a prehospital and/or trauma registry.
          • TXA dosing, timing, Blood transfusion requirements, and any adverse events should be included in the registry

  TEG is used to guide resuscitation in some trauma center Fibrinolysis as measured by percent clot lysis at 30 min after reaching maximum clot

  strength should be collected in the trauma registry

  -In the case of trauma patients known to be on chronic anticoagulants

  -The effect of administering TXA in conjunction with other medications used to reverse anticoagulants may lead to more thrombotic complications

  -Children were excluded from the CRASH-2 Trial.

  -The risk of TXA is seizures in pediatric population. Information adopted from ref. [40,41].

  Medical control should be consulted prior to TXA administration if specific protocols for this situation have not been developed.

  Prehospital TXA use in pediatric patients is not currently recommended

  Acknowledgment

  We thank all the research office team at the trauma and vascular sur- gery units at HMC.

  Ethical approval

  N/A.

  Consent to participate

  N/A.

  Consent for publication

  N/A.

  Availability of data and material

  N/A.

  Competing interests

  The authors have no conflict of interest, no financial issues to dis- close and no funding was received for this study.

  Funding

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

  Author’s contribution

  All authors contributed substantially in the design of the study interpretation of the data, writing the manuscript and approving the submission.

  References

  1. World Health Organization. Injuries. Health topics. [Cited on 18-09-2017]. Available at: http://www.who.int/topics/injuries/en/.
  2. Centers for Disease Control and Prevention. WISQARS – leading causes of death reports, national and regional, 1999-2014. [Cited on 18-09-2017]. Available at: http://www.cdc.gov/injury/wisqars/; 2015.
  3. Perel P, Prieto-Merino D, Shakur H, Clayton T, Lecky F, Bouamra O, et al. Predicting early death in patients with traumatic bleeding: development and validation of prognostic model. BMJ 2012 Aug 15;345:e5166.
  4. Sobrino J, Shafi S. Timing and causes of death after injuries. Proc (Baylor Univ Med Cent) 2013;26(2):120-3.
  5. Niles SE, McLaughlin DF, Perkins JG, Wade CE, Li Y, Spinella PC, et al. Increased mor- tality associated with the early coagulopathy of trauma in combat casualties. J Trau- ma 2008;64(6):1459-63 (1463-5).
  6. Kauvar D, Lefering R, Wade C. Impact of hemorrhage on trauma outcome: an over- view of epidemiology, clinical presentations, and Therapeutic considerations. J Trau- ma 2006;60(6 Suppl):S3-11.
  7. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, et al. Epidemiology of Trauma deaths: a reassessment. J Trauma 1995;38(2):185-93.
  8. Paudyal P, Smith J, Robinson M, South A, Higginson I, Reuben A, et al. Tranexamic acid in major trauma: implementation and evaluation across South West England. Eur J Emerg Med 2017;24(1):44-8.
  9. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy pre- dicts mortality in trauma. J Trauma 2003;55(1):39-44.
  10. 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. Prehosp Emerg Care 2015; 19(1):79-86.
  11. Chatrath V, Khetarpal R, Ahuja J. fluid management in patients with trauma: restrictive versus liberal approach. J Anaesthesiol Clin Pharmacol 2015 Jul- Sep;31(3):308-16.
  12. CRASH-2 trial collaboratorsShakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. 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 2010;376(9734):23-32.
  13. CRASH-2 collaboratorsRoberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The im- portance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377(9771) (1096-101.1101.e1-2).
  14. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. The CRASH-2 trial: a randomized controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess 2013;17(10):1-79.
  15. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study. Arch Surg 2012;147(2):113-9.
  16. Zickenrott V, Greb I, Henkelmann A, Balzer F, Casu S, Kaufner L, et al. Tranexamic acid in the German emergency medical service: a national survey. Anaesthesist 2017 Apr;66(4):249-55.
  17. Neeki MM, Dong F, Toy J, Vaezazizi R, Powell J, Jabourian N, et al. Efficacy and safety of tranexamic acid in prehospital traumatic hemorrhagic shock: outcomes of the Cal-PAT study. West J Emerg Med 2017 Jun;18(4):673-83.
  18. Wafaisade A, Lefering R, Bouillon B, Bohmer AB, Gassler M, Ruppert M, et al. Prehospital administration of tranexamic acid in trauma patients. Crit Care 2016; 20:143.
  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 med- ical evacuation. Air Med J 2013;32(5):289-92. https://doi.org/10.1016/j.amj. 2013.05.001.
  20. Nadler R, Gendler S, Benov A, Strugo R, Abramovich A, Glassberg E. Tranexamic acid at the point of injury: the Israeli combined civilian and military experience. J Trauma Acute Care Surg 2014;77(Suppl. 2):S146-50.
  21. Lipsky AM, Abramovich A, Nadler R, Feinstein U, Shaked G, Kreiss Y, et al. Tranexamic acid in the prehospital setting: Israel Defense Forces’ initial experience. Injury 2014;45(1):66-70.
  22. Mrochuk M, ODochartaigh D, Chang E. Rural trauma patients cannot wait: tranexamic acid administration by helicopter emergency medical services. Air Med J 2015;34(1):37-9.
  23. Schauer SG, April MD, Naylor JF, Wiese J, Ryan KL, Fisher AD, et al. Prehospital administration of tranexamic acid by ground forces in Afghanistan: the Prehospital Trauma Registry experience. J Spec Oper Med 2017;17(3):55-8.
  24. Kunze-Szikszay N, Krack LA, Wildenauer P, Wand S, Heyne T, Walliser K, et al. The pre-hospital administration of tranexamic acid to patients with multiple injuries and its effects on rotational thrombelastometry: a prospective observational study in pre-hospital emergency medicine. Scand J Trauma Resusc Emerg Med 2016; 24(1):122.
  25. Yeguiayan J, Rosencher N, Vivien B. Early administration of tranexamic acid in trau- ma patients. Lancet 2011;378(9,785):27-8.
  26. Kakar PN, Gupta N, Govil P, Shah V. Efficacy and safety of tranexamic acid in control of bleeding following TKR: a randomized control trial. Indian J Anaesth 2009;53: 667-71.
  27. Movafegh A, Eslamian L, Dorabadi A. Effect of intravenous tranexamic acid adminis- tration on blood loss during and after cesarean delivery. Int J Gynaecol Obstet 2011; 115:224-6.
  28. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012 May 17; 344:e3054. https://doi.org/10.1136/bmj.e3054.
  29. Zehtabchi S, Abdel Baki SG, Falzon L, Nishijima DK. Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis. Am J Emerg Med 2014 Dec; 32(12):1503-9. https://doi.org/10.1016/j.ajem.2014.09.023.
  30. Gausden EB, Qudsi R, Boone MD, O’Gara B, Ruzbarsky JJ, Lorich DG. Tranexamic acid in orthopaedic trauma surgery: a meta-analysis. J Orthop Trauma 2017;31(10): 513-9.
  31. Pinto MA, da Silva JG, Chedid AD, Chedid MF. Use of tranexamic acid in trauma pa- tients: an analysis of cost-effectiveness for use in Brazil. Arq Bras Cir Dig 2016;29(4): 282-6. https://doi.org/10.1590/0102-6720201600040017.
  32. Van Haren RM, Valle E, Busko AM, Guarch GA, Jouria JA, Namias N, et al. Safety and efficacy of tranexamic acid in trauma patients at high risk for venous thromboembo- lism. J Am Coll Surg 2013;217(S49). https://doi.org/10.1016/j.jamcollsurg.2013.07. 099.
  33. Gruen R. Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH Study) (PATCH). ClinicalTrials.gov. Identifier: NCT02187120. [Cited on 18-09-2017]. Available at: https://clinicaltrials.gov/ct2/show/NCT02187120?term= NCT02187120&rank=1.
  34. May S. Prehospital tranexamic acid use for traumatic brain injury (TXA). ClinicalTrials.gov. Identifier: NCT01990768. [Cited on 18-09-2017]. Available at: https://clinicaltrials.gov/ct2/show/NCT01990768.
  35. Sperry J. Study of Tranexamic Acid During Air Medical Prehospital Transport Trial (STAAMP Trial) (STAAMP). ClinicalTrials.gov. Identifier: NCT02086500. [Cited on 18-09-2017]. Available at: https://clinicaltrials.gov/ct2/show/ NCT02086500.
  36. Huebner BR, Dorlac WC, Cribari C. Tranexamic acid use in prehospital uncontrolled hemorrhage. Wilderness Environ Med 2017 Jun;28(2S):S50-60.
  37. Chapman MP, Moore EE, Ramos CR, Ghasabyan A, Harr JN, Chin TL, et al. Fibrinolysis greater than 3% is the critical value for initiation of antiFibrinolytic therapy. J Trauma Acute Care Surg 2013;75(6):961-7.
  38. Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma: how should we use it? J Trauma Acute Care Surg 2013 Jun;74(6):1575-86.
  39. Stein P, Studt JD, Albrecht R, Muller S, von Ow D, Fischer S, et al. The impact of prehospital tranexamic acid on blood coagulation in trauma patients. Anesth Analg 2017 Dec 11. https://doi.org/10.1213/ANE.0000000000002708.
  40. Fischer PE, Bulger EM, Perina DG, Delbridge TR, Gestring ML, Fallat ME, et al. Guid- ance document for the prehospital use of tranexamic acid in injured patients. Prehosp Emerg Care 2016;20(5):557-9.
  41. Thurston B, Chowdhury S, Edu S, Nicol AJ, Navsaria PH. Time since injury is the major factor in preventing tranexamic acid use in the trauma setting: an observational co- hort study from a major trauma centre in a middle-income country. S Afr J Surg 2015 Oct 8;53(1):13-8.
  42. Valentine JC, Pigott TD, Rothstein HR. How many studies do you need? A primer on statistical power for meta-analysis. J Educ Behav Stat 2010;35(2):215-47. https:// doi.org/10.3102/1076998609346961.