American Journal of Emergency Medicine xxx (2016) xxxxxx

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American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

Comparison of tranexamic acid plasma concentrations when administered via

intraosseous and intravenous routes
Sren R. Boysen a,, Jessica M. Pang a, John R. Mikler b, Cameron G. Knight a, Hugh A. Semple b, Nigel A. Caulkett a
a
Department of Veterinary Clinical and Diagnostic Sciences, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta T2N 4Z6, Canada
b
Defence Research and Development Canada Sufeld Research Centre, Box 4000, Station Main, Medicine Hat, Alberta T1A 8K6, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: There is a lack of information regarding intraosseous (IO) administration of tranexamic acid (TXA).
Received 19 August 2016 Our hypothesis was that a single bolus IO injection of TXA will have a similar pharmacokinetic prole to TXA
Received in revised form 18 October 2016 administered at the same dose IV.
Accepted 22 October 2016 Methods: Sixteen male Landrace cross swine (mean body weight 27.6 2.6 kg) were divided into an IV group
Available online xxxx
(n = 8) and an IO group (n = 8). Each animal received 30 mg/kg TXA via an IV or IO catheter, respectively. Jug-
ular blood samples were collected for pharmacokinetic analysis over a 3 h period. The maximum TXA plasma
Keywords:
Intraosseous
concentration (Cmax) and corresponding time as well as distribution half-life, elimination half-life, area under
Intravenous the curve, plasma clearance and volume of distribution were calculated. One- and two-way analysis of variance
Pharmacokinetic for repeated measures (time, group) with Tukey's and Bonferonni post hoc tests were used to compare TXA
EZ-Io plasma concentrations within and between groups, respectively.
Io Results: Plasma concentrations of TXA were signicantly higher (p b 0.0001) in the IV group during the TXA
Intraosseous catheter infusion. Cmax occurred at 4 min after initiation of the bolus in the IV group (9.36 3.20 ng/l) and at 5 min
after initiation of the bolus in the IO group (4.46 0.49 ng/l). Plasma concentrations were very similar from
the completion of injection onwards. There were no signicant differences between the two administration
routes for any other pharmacokinetic variables measured.
Conclusion: The results of this study support pharmacokinetic bioequivalence of IO and IV administration of TXA.
2016 Elsevier Inc. All rights reserved.

1. Introduction underscores the need to establish effective routes of administration to

Following promising preliminary results from human studies such
as the CRASH-2 and MATTERs studies, administration of intravenous
(IV) tranexamic acid (TXA), an anti-brinolytic agent, is currently in-
cluded in several civilian and military human trauma and resuscitation
protocols [1,2]. Military Damage-Control Resuscitation Clinical Practice
Guidelines state that the early use of IV TXA should be strongly consid-
ered for any patient requiring blood products in the treatment of
combat-related hemorrhage and is most strongly advocated in patients
judged likely to require massive transfusion [2,3]. Although these stud-
ies suggest that early administration of TXA (1 h following trauma) is
associated with the greatest decrease in hemorrhage-related deaths,
there is also evidence to suggest that its administration 3 h after injury
may be harmful [1]. The narrow therapeutic timeline for TXA
Funding: Public Works Canada, Defence Research and Development Canada (W7702-
145634/A).
Corresponding author.
E-mail address: srboysen@ucalgary.ca (S.R. Boysen).
ensure trauma patients receive TXA in a timely fashion.
Several current guidelines state that if resuscitation is required and
IV access is not obtainable, the intraosseous (IO) route should be used
for certain medications [3,4]. Given the safety of administration of
other medications via the IO route, and the fact that TXA has a pH similar
to that of sodium chloride 0.9% solution and blood products [5], the use
of IO TXA has been suggested should IV access not be available [4,6].
Despite evidence supporting the IO administration of drugs, there is a
paucity of literature regarding the administration of IO TXA as a life-
saving option in cases of failed or impossible IV catheterization [7].
The limited use of TXA via the IO route is likely explained by the fact
that it has not been established if alternative routes of administration of
TXA (i.e., IO, intramuscular, etc.) provide the same benets that have
been prospectively demonstrated with the IV route [5]. This has led to
some authors cautioning against the use of IO TXA as equivalency
between IO and IV routes has not been established and Pzer
recommends only intravenous administration, for which the detailed
pharmacokinetics of TXA have been demonstrated [8]. It is apparent
that studies investigating the administration of IO TXA are needed. In
fact, on the initiative of the American military, a group of panel experts

http://dx.doi.org/10.1016/j.ajem.2016.10.054
0735-6757/ 2016 Elsevier Inc. All rights reserved.

Please cite this article as: Boysen SR, et al, Comparison of tranexamic acid plasma concentrations when administered via intraosseous and
intravenous routes, American Journal of Emergency Medicine (2016), http://dx.doi.org/10.1016/j.ajem.2016.10.054
2 S.R. Boysen et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx

recently identied potential routes of TXA administration (IV, oral, IO,
transmucosal) as a Priority 2 research requirement [5].
The objective of this study was to determine if plasma levels of TXA
are similar when given IO versus IV. We hypothesised that a single bolus
IO injection of TXA will have a similar pharmacokinetic prole to TXA
administered at the same dose IV.
2. Methods
This study was approved by the University of Calgary Animal Care
Committee (Protocol AC15-0068) and the animals were managed in ac-
cordance with the Canadian Council on Animal Care standards.
2.1. Animal Preparation
placed over the right adductor muscle. Rectal body temperature was
measured with a pliable rectal probe (Datex-Ohmeda s/5 Collect, GE
Healthcare, Helsinki, Finland FIN-00031) and maintained between 37
and 38 C using a circulating water pad as needed.
The IO TXA animals received an IO catheter (Arrow EZ-IO, pediatric,
pink 15 G 15 mm, Teleex Incorporated, Wayne, PA) that was inserted
by a single experienced operator into the right proximal tibia just medial
to the tibial tuberosity. A power drill (Arrow EZ-IO, Power Driver G3,
Teleex Incorporated, Wayne, PA) was used and a 90 angle to the bone
surface was maintained during insertion. The stylet was removed, blood
was observed back-owing through the hub, and an extension set was
attached (EZ Connect, Teleex Incorporated, Wayne, PA). A small
amount of blood was aspirated and the catheter was ushed with 20 ml
heparinized saline to ensure patency.

Sixteen male Landrace-Large White cross swine with a mean body 2.4. Experimental Design
weight of 27.6 2.6 kg were included in the study. The pigs were
sourced from a commercial swine production unit, housed individually Sixteen animals were used in the study and all were included in the
or in groups of 2 and fed a pelleted swine ration twice daily with ad data analysis. Animals were divided into two groups. Each pig in the IV
libitum access to nipple water feeders. Each pig was kept in an individ- group (n = 8) received 30 mg/kg of IV TXA (Tranexamic Acid
ual pen and fasted with ad libitum access to water for twelve hours be- 100 mg/ml, Sandoz, QC, Canada, J4B 7 K8), followed by a 1 ml/kg saline
fore premedication. bolus. Each pig in the IO group (n = 8) received 30 mg/kg TXA via the IO
catheter followed by a 1 ml/kg saline bolus. The TXA dose was made up
2.2. Anesthesia to a total of 25 ml using saline as the diluent in both groups and the so-
lution was administered over 5 min using a digitally programmable sy-
Swine were premedicated with intramuscular (IM) azaperone 6 mg ringe driver. The saline bolus was manually administered over 1 min.
(Stresnil 40 mg/ml, Vtoquinol Inc., Lavaltrie, QC, Canada J5 T 3S5), None of the observers were blinded to treatment. The experimental
dexmedetomidine 0.6 mg (Dexdomitor 0.5 mg/ml, Zoetis Inc., Kalama- protocol was divided into 2 phases. A detailed data collection timeline is
zoo, MI, USA 49007) and alfaxalone 60 mg (Alfaxan 10 mg/ml, Jurox shown in Table 1. The rst 30 min established anesthetic and physiolog-
Pty Ltd., Rutherford, NSW, Australia 2320). Swine were weighed prior ic equilibration prior to the second phase. During the second phase
to induction of anesthesia. A 22 gauge (G), two-port catheter (BD Saf- physiologic recording and blood sampling were conducted. Data includ-
T-Intima IV Catheter, Becton Dickinson, Sandy, UT, USA 84070) was ing heart rate, ECG, direct arterial blood pressure, end tidal CO2, BIS, tis-
placed in an auricular vein of both ears and induction was completed sue oxygen saturation, respiratory rate, tidal volume, minute volume,
with 12 mg/kg IV alfaxalone, titrated to effect. Animals receiving IV and rectal temperature were collected continuously. Arterial blood
TXA had one ear marked TXA in permanent ink to ensure that that
particular auricular catheter was dedicated to the TXA bolus only.
Anesthesia was delivered using a circle system with isourane (FIIso Table 1
Timeline for pharmacokinetic, arterial blood gas, and physiologic data collection prior to
1.32%) and oxygen (FIO2 100%). Two constant rate infusions and following intraosseous (IO, n = 8) and intravenous (IV, n = 8) tranexamic acid
(alfaxalone 25 g/kg/min and dexmedetomidine 2 g/kg/h) were ad- (TXA) administration of 30 mg/kg over 5 min and a total jugular venous sampling period
ministered via one of the auricular catheters using digitally programma- of 3 h. Intravenous injection was via an auricular vein and IO infusions were through the
ble syringe drivers (Medfusion 3500, Smiths Medical International, St. right proximal tibia.
Paul, MN, USA 55112). A 7.5 ml/kg/h continuous rate infusion (CRI) of Time point Description Data collected
0.9% saline (1000 ml 0.9% Sodium Chloride, Baxter Corp, Mississauga
SSA Steady state anesthesia pK, ABG, PP
ON, Canada L4Z 3Y4) was administered for the duration of the experi- Baseline (BL) Immediately before TXA bolus pK, ABG, PP
ment into the TXA-designated auricular catheter to maintain patency. Ti TXA bolus 1 min pK, PP
Tii TXA bolus 2 min pK, PP
2.3. Instrumentation Tiii TXA bolus 3 min pK, PP
Tiv TXA bolus 4 min pK, PP
Tv TXA bolus 5 min pK, ABG, PP
Instrumentation included a 5-lead electrocardiogram (ECG), buccal T1 Post TXA bolus + 1 min, end saline bolus pK, PP
pulse oximeter, sidestream capnograph, spirometer, tissue oxygen satu- T2 Post TXA bolus + 2 min pK, PP
ration monitor, bispectral index (BIS) and a rectal thermometer. The T4 Post TXA bolus + 4 min pK, PP
T6 Post TXA bolus + 6 min pK, PP
ECG, pulse oximeter, capnograph and spirometry data were displayed
T8 Post TXA bolus + 8 min pK, PP
and recorded with a multiparameter monitor (Datex-Ohmeda s/5 Col- T10 Post TXA bolus + 10 min pK, ABG, PP
lect, GE Healthcare, Helsinki, Finland FIN-00031). The BIS electrodes T15 Post TXA bolus + 15 min pK, ABG, MVBG, PP
(BIS Pediatric Sensor, Covidien LLC, 15 Hampshire Street, Manseld, T20 Post TXA bolus + 20 min pK, ABG, PP
MA, U.S.A. 02 048) were placed horizontally across a clipped area of T25 Post TXA bolus + 25 min pK, ABG, PP
T30 Post TXA bolus + 30 min pK, PP
skin overlying the frontal bone and right lateral aspect of the skull and
T45 Post TXA bolus + 45 min pK, ABG, MVBG, PP
connected to a BIS monitor (BIS Vista Monitoring System, Aspect T60 Post TXA bolus + 60 min pK, ABG, PP
Medical Systems, Norwood, MA, USA 02062). Animals were placed T80 Post TXA bolus + 80 min pK, ABG, PP
into dorsal recumbency for the duration of the study. T100 Post TXA bolus + 100 min pK, ABG, PP
T120 Post TXA bolus + 120 min pK, ABG, PP
One common carotid artery was catheterized to perform intermit-
T150 Post TXA bolus + 150 min pK, ABG, PP
tent arterial blood gas analysis and continuous arterial blood pressure T180 Post TXA bolus + 180 min pK, ABG, PP
monitoring (systolic, diastolic and mean). An external jugular vein
PP: physiologic parameters including cardiac and respiratory values, tissue oxygen satura-
was also catheterized to allow TXA blood sampling. A tissue saturation tion, rectal body temperature, and bispectral index data were collected continuously; pK:
sensor (Inspectra StO2 Sensor, model 1615, Hutchinson Technology, jugular venous sample for pharmacokinetic analysis; ABG: arterial blood gas; MVBG:
40 West Highland Park Drive NE, Hutchinson, MN, USA 55350) was mixed venous blood gas.

Please cite this article as: Boysen SR, et al, Comparison of tranexamic acid plasma concentrations when administered via intraosseous and
intravenous routes, American Journal of Emergency Medicine (2016), http://dx.doi.org/10.1016/j.ajem.2016.10.054
 S.R. Boysen et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx
samples were intermittently collected throughout the study. Jugular ve-
nous blood samples were collected for pharmacokinetic (pK) analysis in
the following sequence: during steady state anesthesia (SSA), at base-
line (BL) immediately before TXA injection, every one minute during
TXA injection (Ti-v), and 1, 2, 4, 6, 8, 10, 15, 20, 25, 30 45, 60, 80, 100,
120, 150 and 180 min (T1180) after TXA injection (Table 1).
Each sample was either processed immediately or stored in an ice
bath for a maximum of 10 min. A single operator processed all of the
samples. Vacutainer tubes were centrifuged at 3600 RPM for 10 min at
4 C. A pipette was used to draw off the plasma and duplicate cryovials
were lled with 0.5 ml plasma. The cryovials were submerged in liquid
nitrogen, removed, and immediately placed into a 80 C freezer.
2.5. Euthanasia and Pathological Examination
Upon completion of the experiment, isourane was increased to 4%
for 10 min and animals were euthanized with 12 ml of a saturated KCL
solution administered via IV injection. Following euthanasia, both pelvic
limbs were disarticulated at the stie joint in the IO group and the distal
portion of the limbs were immediately placed on ice and submitted to a
USA board-certied anatomic pathologist (CK) for gross and microscop-
ic examination of the tibial medullary cavities.
Each tibia was clamped in a vice and a double-bladed saw was used
to cut a 5 mm thick longitudinal slab that included the proximal tibial
epiphysis, the growth plate, and the proximal one third of the
metaphysis. For the right tibia the slab included the catheter introduc-
tion site; for the left tibia the slab mirrored that taken from the right
side. Slabs were decalcied in 20% formic acid for 23 days until
sufciently softened to be trimmed with a scalpel blade. After decalci-
cation, an approximately 20 30 mm section was cut from each slab,
embedded in in parafn, and prepared routinely for histologic examina-
tion using hematoxylin and eosin stain. Each histologic section included
proximal tibial articular cartilage, epiphysis, growth plate and
metaphysis.
Sections from the right tibial slab were cut in such a way that the
catheter path within the metaphyseal cortex was avoided; the purpose
of this was to assess potential bone marrow lesions caused by drug
toxicity rather than by catheter insertion trauma. Bone marrow in
each section was assessed microscopically in a blinded manner (left
versus right side) according to previously published methods [9,10].
2.6. Determination of Plasma Tranexamic Acid Concentrations
The materials used included acetonitrile and methanol LC/MS grade
(Sigma-Aldrich, Mississauga, ON, Canada L6H 6J8), formic acid ACS
grade (EMD-Millipore Ltd., Toronto, ON, Canada L6H 6J8), TXA for IV
injections preservative free (Tranexamic Acid 100 mg/ml, Sandoz, QC,
Canada, J4B 7K8) and ultrapure water (18.2 M). Plasma samples
were thawed at 37 C for 10 min and vortexed. Proteins were precipitat-
ed by mixing 100 l of the plasma sample with 300 l of ice cold
methanol. Mixtures were incubated at 20 C for 20 min prior to cen-
trifugation at 17 000 g for 10 min. A 40 l aliquot of the supernatant
was added to 960 l of methanol in 1 ml auto-sampler vials. These sam-
ples were stored at 20 C prior to analysis. The analytical LC/MS for
the quantication of TXA consisted of Agilent 1200 LC (binary pump,
standard auto injector, and temperature-controlled column compart-
ment) coupled with Agilent MS TOF 6230.
The separation was performed on an Agilent 1200 HPLC with a
Zorbax eclipse XDB-C18 column. The column temperature was set at
40 C. The mobile phase consisted of Buffer A (10 mM formic acid in
water) and Buffer B (10 mM formic acid in 90% acetonitrile). Injection
volume was 1 l. A linear gradient elution was performed at a ow
rate of 0.4 ml/min, with gradient changes at 0 min of 3% Buffer B, at
8 min to 85% Buffer B, at 10 min to 100% Buffer B and at 12 min to 3%
Buffer B.
Please cite this article as: Boysen SR, et al, Comparison of tranexamic acid plasma concentrations when administered via intraosseous and
intravenous routes, American Journal of Emergency Medicine (2016), http://dx.doi.org/10.1016/j.ajem.2016.10.054
3
The mass spectral analysis was performed on an Agilent 6230 TOF
MS controlled by MassHunter software. The instrument was operated
in positive mode using electron ionization (EI) source and following
operational settings: gas temperature of 300 C, gas ow of 4 l/min,
nebulizer at 50 psi, sheath gas temperature at 250 C, sheath gas ow
at 10 l/min, nozzle voltage at 500 V and fragmentor voltage of 90 V.
The limit of detection (LOD) in plasma was 0.01 g/ml.
2.7. Pharmacokinetic Analysis
The pharmacokinetic analyses were performed with PK Solutions
using a non-compartmental pK method. Plasma concentration versus
sampling time data were plotted for each animal and pharmacokinetic
parameters were calculated. The maximum TXA plasma concentration
for each animal (Cmax) and its corresponding time (Tmax) were reported
directly from the assay data following administration by each route.
Individual elimination rates (kel) were determined by linear regression
of the respective natural logarithm of TXA plasma concentrations versus
time during the terminal phase. The following variables
were determined: distribution half-life (t1/2 D), elimination half-life
(t1/2 E), area under the curve (AUC), plasma clearance (Clp; where
Clp = Dose / AUC(0)), and volume of distribution (Vd; where Vd =
Dose / AUC(0) kel).
2.8. Statistical Analyses
All data were reported as mean plus or minus one standard devia-
tion (SD) unless otherwise stated. Plasma concentration graphs were
plotted as mean plus or minus one standard error mean (SEM).
Shapiro-Wilk analysis was used to test data for normality. Parametric
analyses were used where data approximated normal distribution. Var-
iables compared over time and between groups were analyzed with one
and two-way analysis of variance for repeated measures (time, group)
with Tukey's and Bonferonni post hoc tests, respectively. Differences
in body weight, drug dosage and pharmacokinetic parameters were an-
alyzed with a Mann-Whitney U test. Derived pharmacokinetic compar-
isons were plotted as median plus or minus interquartile range (IQR).
Differences were considered signicant at p 0.05. Statistical analyses
were performed with GraphPad Prism 5.04 (GraphPad Prism, La
Jolla, CA, USA 92037).
3. Results
Data from all sixteen animals (n = 8 per group) were used in the
study with the exception of the arterial blood gas (ABG) analyses,
where some data points were missing. There were a total of 5 ABG
data points missing for time point Tv (2 in the IV group and 3 in the
IO group) and all data for this time point were excluded from ABG
statistical analysis. There were also missing ABG data points at T5 in
one swine from the IV group, and at T120, T150, and T180 from another
swine in the IV group. This resulted in only 6 swine being included in
ABG statistical analysis in the IV group. There were no signicant differ-
ences in body weight or premedication doses of alfaxalone, azaperone
or dexmedetomidine between the IO and IV groups (2.06 +/ 0.24,
0.21 +/ 0.02, 0.02 +/ 0.0, and 2.19 +/ 0.26, 0.22 +/ 0.02,
0.02 +/ 0.0 mg/kg, respectively). Mean body weight ( SD) was
28.8 2.4 and 26.5 2.4 kg in the IO and IV groups, respectively.
There was no signicant difference between total dose of TXA
administered (p = 0.08). Mean TXA doses (mg) were 863 72 (IO)
and 795 72 (IV).
3.1. Catheter Placements
There were no complications associated with auricular venous or
tibial IO catheterization. All IO catheters were inserted on the rst
attempt by the same investigator.
4 S.R. Boysen et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx

3.2. Physiologic Parameters 3.4. Tibial Bone Marrow Pathology

There were no signicant differences between IO and IV groups for
any cardiovascular parameters, rectal temperature, bispectral index or
tissue oxygenation. However, within each group there was a statistically
signicant variation in heart rate, arterial blood pressure, temperature,
BIS and STO2 over time. These changes were not clinically signicant
or acutely related to TXA administration. A sub-analysis was performed
for mean heart rate as well as systolic, diastolic and mean arterial blood
pressures over the ve minute TXA injection period for both IO and IV
groups. There were no signicant differences over time or between
groups for any of these parameters.
There were no signicant differences between IO and IV groups for
respiratory rate or arterial blood gas parameters. Within each group
there were statistically signicant variations in respiratory rate (n = 8
per group), and the following blood gas parameters over time (n = 6
IV, n = 8 IO); pH, partial pressure of arterial carbon dioxide, partial pres-
sure of arterial oxygen, hemoglobin, sodium, arterial bicarbonate, and
extracellular base excess (Table 2a, Table 2b). The changes were
relatively small and considered clinically insignicant.
3.3. Pharmacokinetic Parameters
Pharmacokinetic data were collected and analyzed for all 16 animals.
Changes in plasma concentration over time are shown in Fig. 1. Plasma
concentrations of TXA were signicantly higher (p b 0.0001) in the IV
group during the TXA infusion (Figs. 1 & 2). Mean ( SD) plasma TXA
concentrations (ng/l) over this interval were 7.25 1.93 and 2.55
1.61, respectively. Peak plasma concentrations (Cmax) occurred 4 min
after initiation of the bolus in the IV group (mean SD: 9.36
3.20 ng/l; range: 3.7113.01 ng/l) and at 5 min post-bolus in the IO
group (mean SD: 4.46 0.49 ng/l; range: 3.635.13 ng/l). Peak
concentration for TXA was therefore 52% lower with IO administration
compared to IV when a mean ratio was calculated (Table 3). Plasma
concentrations were very similar from T1 (completion of the saline
bolus post TXA administration) onwards (Fig. 1).
There were no signicant differences between the two administra-
tion routes for any other direct or calculated pharmacokinetic variable.
Volume of distribution was moderately more variable in the IO group
(Fig. 3). One IO pig also had signicantly higher plasma clearance com-
pared to all other animals (Fig. 4). Comparison of intraosseous/intrave-
nous ratios of mean AUC(0) values indicated that IO administration
only resulted in a 5% lower exposure to TXA compared to the IV route
(Fig. 5, Table 3).
Right and left tibias from all pigs in the IO group were examined.
Bone marrow was histologically normal in all sections. There was no dif-
ference in marrow between the right (catheterized) and left tibia for
any animal.
4. Discussion
In emergency settings where patients are in shock with collapsed
peripheral circulation, alternative routes such as IO catheters may be re-
quired to improve patient outcome [11,12]. It is therefore essential to
know if medications administered intraosseously can be given at the
same dose and rate to achieve the same clinical benet as the IV route.
Although intravenous TXA has been used in various porcine experimen-
tal models [13-15], the only documented use of IO TXA administration
in pigs involved cadaver limbs [16]. The current study is the rst pub-
lished report comparing pharmacokinetic characteristics of IO and IV
TXA in any species. The results of this study support bioequivalence of
TXA when administered IO or IV in swine, and support previously de-
scribed pharmacokinetic characteristics of IV administered TXA [17-19].
Given that studies suggest there is a limited therapeutic window in
which the administration of TXA has a benecial effect [1], the peak con-
centration (Cmax) and time to peak concentration (Tmax) of TXA are clin-
ically important to assess. In the current study, the IV route reached Cmax
4 min after initiating the bolus injection, which was 1 min earlier than
the IO route. The disparity in TXA plasma concentrations and Cmax dur-
ing the ve minute bolus period in this study was most likely due to the
proximity of the auricular venous circulation versus the tibial circulation
relative to the jugular catheter sampling site. The short lag time be-
tween infusing the bolus and collecting serial venous samples likely
did not allow for adequate vascular and corporeal mixing at the IV injec-
tion site before reaching the sampling site [20]. Plasma concentrations
during this interval in the IV group therefore most likely represented
drug streaming and subsequent withdrawal of unmixed TXA. We hy-
pothesis that mixed venous or arterial sampling sites may eliminate
drug streaming if the auricular vein is used for TXA administration
during TXA pharmacokinetic studies. Alternatively, if the jugular site is
chosen for IV TXA pharmacokinetic study sampling, other IV drug ad-
ministration sites that drain into the inferior vena cava (i.e. femoral
vein), may allow sufcient mixing of TXA and blood to eliminate the
risk of drug streaming. Further studies are required to conrm these
hypotheses. The tibial IO catheter was likely a sufcient distance from
the jugular circulation so the sampling intervals were inconsequential
and adequate mixing occurred prior to blood collection. Therefore, it

Table 2a
Mean (SD, underneath) physiologic and arterial blood gas parameters following porcine auricular intravenous (IV n = 6) bolus administration of 30 mg/kg tranexamic acid over 5 min at
various time points during a jugular venous sampling period of 3 h.

SSA BL Tv T10 T15 T20 T30 T60 T80 T120 T150 T180

PH 7.37 7.38 7.37 7.37 7.38 7.38 7.39 7.39 7.40 7.41 7.40 7.40
0.03 0.03 0.03 0.03 0.03 0.04 0.03 0.03 0.03 0.05 0.04 0.04
pCO2 (mm Hg) 52.5 53.4 53.6 53.0 50.5 49.7 49.8 50.6 49.8 47.8 50.1 48.9
6.6 7.2 7.3 9.0 5.6 4.8 5.2 6.2 4.8 7.0 5.8 6.0
pO2 (mm Hg) 356 349 346 337 339 335 337 320 309 301 302 297
31 31 32 37 39 66 46 45 54 74 76 74
Hgb g/L 110 111 111 109 109 110 110 109 110 109 108 108
9 10 10 8 8 8 6 6 6 6. 6 7
Sodium (mmol/L) 140.5 139.9 140.6 140.8 140.6 140.3 139.7 138.9 139.0 139.3 139.4 139.1
2.6 1.9 2.8 2.1 2.3 2.1 0.9 1.1 1.5 2.0 1.5 1.5
HCO3 (mol/L) 30.3 31.2 31.0 30.7 29.6 29.6 29.8 30.3 30.5 29.8 30.6 30.1
2.5 2.4 2.5 3.1 2.2 1.2 1.5 2.9 1.6 1.7 1.7 1.8
BE (mol/L) 4.7 5.4 5.2 4.4 4.6 4.6 4.7 5.3 5.7 4.8 5.9 5.3
2.6 2.0 2.3 1.9 2.4 1.4 1.6 3.1 1.8 1.3 1.8 1.9
RR (bpm) 26.3 26.8 NA 28.00 NA 29.1 29.5 30.8 31.1 31.6 30.6 30.8
5.8 5.751 NA 6.0 NA 6.1 6.0 6.3 6.0 5.9 5.3 6.5

pCO2: partial pressure of carbon dioxide; pO2: partial pressure of oxygen; Hgb: hemoglobin; HCO3: bicarbonate; BE: base excess; RR: respiratory rate; bpm: breaths per minute; N/A: not
assessed at that time point.

Please cite this article as: Boysen SR, et al, Comparison of tranexamic acid plasma concentrations when administered via intraosseous and
intravenous routes, American Journal of Emergency Medicine (2016), http://dx.doi.org/10.1016/j.ajem.2016.10.054
 S.R. Boysen et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx 5

Table 2b
Mean (SD, underneath) physiologic and arterial blood gas parameters following porcine tibial intraosseous (IO n = 8) bolus administration of 30 mg/kg tranexamic acid over 5 min at
various time points during a jugular venous sampling period of 3 h.

SSA BL Tv T10 T15 T20 T30 T60 T80 T120 T150 T180

PH 7.38 7.38 7.38 7.38 7.38 7.39 7.39 7.40 7.4 7.4 7.40 7.40
0.02 0.02 0.02 0.02 0.02 0.02 0.01 0.02 0.03 0.03 0.02 0.03
pCO2 (mm Hg) 51.9 52.6 53.7 52.7 53.1 51.7 53.2 52.2 50.3 51.0 52.6 52.4
4.7 5.5 5.0 4.1 4.6 4.9 4.2 3.3 4.8 5.8 4.6 5.6
pO2 (mm Hg) 331 329 325 312 295 296. 293 288 281 283 268 265
55 58 54. 69 75 79 69 665 63 67 79 74
Hgb g/L 110 110 109 107 109 106 108 106 106 106 106 105
7 7 7 6 7 5 8 5 88 7 6 9
Sodium (mmol/L) 139.3 139.3 139.5 140.0 139.3 138.1 138.7 137.8 138.2 138.0 138.1 138.3
1.1 1.0 1.5 1.1 1.8 2.0 1.8 1.6 1.7 1.5 1.4 1.1
HCO3 (mol/L) 30.9 31.2 31.9 31.3 31.7 31.2 32.40 32.1 31.4 31.8 32.2 32.0
1.9 2.2 1.7 1.4 1.8 1.9 2.6 1.7 2.5 2.2 1.9 1.9
BE (mol/L) 5.7 5.9 6.6 6.0 6.5 6.0 7.4 7.2 6.6 6.9 7.1 6.9
2.0 2.1 1.7 1.3 1.9 1.9 2.7 1.8 2.6 2.1 1.8 2.1
RR (bpm) 26.3 26.8 NA 28.00 NA 29.1 29.5 30.8 31.1 31.6 30.6 30.8
5.8 5.751 NA 6.0 NA 6.1 6.0 6.3 6.0 5.9 5.3 6.5

pCO2: partial pressure of carbon dioxide; pO2: partial pressure of oxygen; Hgb: hemoglobin; HCO3: bicarbonate; BE: base excess; RR: respiratory rate; bpm: breaths per minute; N/A: not
assessed at that time point.

appears the proximal tibia is a good IO site to administer TXA for phar-
macokinetic studies, and will likely allow sufcient mixing with a jugu-
lar, mixed venous or arterial blood sampling sites.
Despite the statistically signicant difference in Cmax between the IV
and IO routes, this is unlikely to result in a clinically signicant differ-
ence given the plasma concentrations were very similar in both groups
within a minute of completing the injection, and a difference of 1 min to
reach peak plasma concentration should not impact clinical outcome.
The pharmacokinetic results of our study are not surprising given
dye and radioactive tracer studies indicate that drugs given via an IO
catheter enter the central circulation within seconds, comparable to ad-
ministration via peripheral IV catheters [21]. Several previous studies
have demonstrated pharmacokinetic equivalence for a number of
drugs given IO versus IV. For example, morphine (human), rocuronium
(swine), atropine (swine) and epinephrine (swine, dogs) have demon-
strated equivalent therapeutic plasma concentrations and pharmacoki-
netic endpoints when administered intraosseously compared to
intravenously [11,22-25]. Evidence also suggests there are no clinically
relevant differences in drug kinetics between IO and IV-administered
medications in hypo- and normovolemic states. However, most of
these studies were conducted using tracer dyes, and under very con-
trolled hemorrhagic models, which may not equate to TXA or more se-
vere states of cardiovascular collapse [26,27].
Non-IV routes of administration for uids and medications have
been advocated in mass casualty settings [28] and IO administration is
currently recommended as an alternative to IV drug administration in
human cases of arrest [29,30]. The high rst attempt success rate,
rapid ability to place IO catheters and simplicity of newer IO devices
make the IO route an attractive option in the prehospital and hospital
setting for both uid resuscitation and drug therapy [28,31-33]. Further-
more, numerous studies have shown that the pharmacological effects of
drugs, such as epinephrine on heart rate and blood pressure, are equiv-
alent when given via either route [24,34].
Despite evidence to suggest medications can be given via the
intraosseous route, the only documented case of IO TXA administration
in humans was reported in a military setting [7]. A 2015 retrospective
analysis of 1000 uses of IO access described IO delivery of TXA in 82 pa-
tients [7]. All but 4 of these patients received IO TXA during helicopter
evacuations performed by Defense Military Services in Iraq and
Afghanistan. These casualties received IO catheters either as a primary
choice in the case of blast-induced traumatic amputation or following

Fig. 1. Plasma concentration (mean SEM) versus time proles (0 3h) after
intravenous (n = 8) and intraosseous (n = 8) bolus administration of tranexamic acid
(TXA; 30 mg/kg over 5 min; Ti to Tv) in swine. Intravenous (IV) TXA administration was
via an auricular vein. Intraosseous (IO) infusion was performed through the right
proximal tibia. TXA was diluted to 25 ml with saline in both groups. BL: Baseline.
Fig. 2. Plasma concentration (mean SEM) versus time proles during the interval of
tranexamic acid (TXA) infusion (30 mg/kg over 5 min; Ti to Tv) using intravenous (n =
8) and intraosseous (n = 8) routes of administration in swine. Plasma concentration
changed signicantly over time () in both groups (p b 0.0001). TXA plasma
concentrations were signicantly higher (*) in the intravenous (IV) group (p b 0.0001)
compared to the intraosseous (IO) group at Ti (p b 0.01), Tii to Tiv (p b 0.0001) and Tv
(p b 0.05). TXA was diluted to 25 ml with saline in both groups. BL: Baseline.

Please cite this article as: Boysen SR, et al, Comparison of tranexamic acid plasma concentrations when administered via intraosseous and
intravenous routes, American Journal of Emergency Medicine (2016), http://dx.doi.org/10.1016/j.ajem.2016.10.054
6 S.R. Boysen et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx
Table 3
Mean (SD) pharmacokinetic values following porcine tibial intraosseous (IO) and auric-
ular intravenous (IV) bolus administration of 30 mg/kg tranexamic acid over 5 min and a
total jugular venous sampling period of 3 h (IO n = 8, IV n = 8).
Parameter IO route (SD) IV route (SD) IO/IV
AUC(0) (g-min/ml) 228.9 51.1 240.6 50.6 0.95
Cmax (ng/l), 4.46 0.49 9.36 3.20 0.48
Tmax (min) 5.00 4.00 1.25
Clp (ml/min/kg) 138.6 39.7 129.2 24.9 1.07
Vd (L/kg) 12.17 2.2 12.20 1.6 1.00
t1/2 Dist (min) 4.0 0.7 3.6 1.0 1.10
t1/2 Elim (min) 62.7 11.1 66.5 8.3 0.94
AUC: area under the curve, Clp: plasma clearance, Vd: volume of distribution, t1/2 Dist:
half-life of distribution, t1/2 Elim: half-life of elimination.
Denotes signicant difference between groups (p = 0.007).
Disparity in these results likely due to a sampling error in the intravenous group
inadequate mixing time from auricular to jugular circulation resulted in partial withdraw-
al of unmixed TXA.
failure of peripheral catheterization. No complications were recorded
and the survival rate was 69.2% [7].
The use of IO TXA has been questioned because there is no evidence
of therapeutic equivalence between IO- and IV-administered TXA [8].
Furthermore, Pzer recommends only IV administration, for which the
pharmacokinetics of TXA have been demonstrated [8]. Our study con-
tributes to the literature regarding the pharmacokinetics of
intraosseously administered TXA and supports this route of administra-
tion in swine models. This does not, however, equate to therapeutic
equivalence and further studies are needed to determine if IO and IV
TXA administration in hemorrhagic shock have the same therapeutic
equivalence.
The pharmacokinetic characteristics of drugs delivered
intraosseously can be altered by drug distribution to the bone marrow
and blood ow to the bone [23]. A trend towards higher variability in
the volume of distribution was observed when using IO administration
in the current study although the difference between groups was not
signicant. Von Hoff et al. reported a signicantly higher Vd in adults re-
ceiving morphine intraosseously compared to intravenously through an
IO cannula in the iliac crest [11]. This nding was attributed to a small
deposition effect near the IO port or in the bone marrow. The depot
effect causes a drug to persist in the IO space, resulting in a lower
peak concentration and a longer time to reach peak concentration
[35]. It has been suggested that any depot effect will be greater when
oil emulsions are used for drug delivery, as these emulsions are believed
to remain in the marrow for longer periods creating a reservoir for drugs
that are slowly liberated and dispensed by the oil [36]. A possible depot
effect is unlikely signicant in the current study as TXA is an aqueous
solution, and ushing the IO catheter with uids following medication
administration is believed to reduce any potential depot effect [36].
Fig. 3. Volume of distribution (median IQR) of tranexamic acid (TXA) following a
30 mg/kg bolus over 5 min and a total jugular venous sampling period of 3 h. The IO
group showed higher variability in volume of distribution compared to IV animals.
Please cite this article as: Boysen SR, et al, Comparison of tranexamic acid plasma concentrations when administered via intraosseous and
intravenous routes, American Journal of Emergency Medicine (2016), http://dx.doi.org/10.1016/j.ajem.2016.10.054
Fig. 4. Plasma clearance (median IQR) of tranexamic acid (TXA) following a 30 mg/kg
bolus over 5 min and a total jugular venous sampling period of 3 h. One pig in the IO
group demonstrated a markedly higher clearance (227.2 ml/min/kg) compared to all
other animals.
However, more hydrophilic drugs that distribute to the bone mar-
row may create an absorption phase that requires dose titrations to
maintain effective plasma concentrations [23]. An absorption phase
due to bone marrow distribution following IO administration of TXA
in the current study seems unlikely as the volume of distribution was
not statistically different between groups and the IO plasma concentra-
tion did not exceed the IV plasma concentration following completion
of drug administration. As the current study only compared a single
bolus injection of TXA, it is unclear if multiple boluses or a CRI of TXA
would have produced similar IO and IV pharmacokinetic results. This
should be investigated further.
A clinically signicant side effect of IV TXA is hypotension as a result
of rapid rates of infusion [37,38]. Injection of 30 mg/kg tranexamic acid
(diluted to a total volume of 25 ml with 0.9% saline) given over 5 min,
either intravenously or intraosseously, had no observable effect on mea-
sured physiologic parameters in the current study. Changes in some
physiologic variables over time most likely reected mild cardiorespira-
tory depression associated with prolonged general anesthesia and dor-
sal recumbency. Decreased blood pressure has been reported in humans
after TXA administration [39,40] but per minute data analysis during
the TXA bolus interval showed no cardiovascular compromise. The
dose and rate of TXA administration used in the current study did not
result in hypotension or have any other detectable negative short
term cardiovascular consequences. It is possible that a higher dose or
rate of administration, repeated boluses, or a CRI would have resulted
in hypotension during infusion of TXA.
The major limitation of this study was the use of a normovolemic,
anesthetized animal model under acute conditions. Although swine
are considered one of the closest experimental equivalents to humans,
these results may not translate to a pediatric or adult patient, particular-
ly if they are in hemorrhagic shock. TXA is eliminated by glomerular
Fig. 5. Area under the curve (AUC) for intravenous (IV) and intraosseous (IO) tranexamic
acid (TXA) administration. IO administration resulted in a 5% lower exposure to TXA
compared to the IV route.
 S.R. Boysen et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx
ltration, and excretion may be altered or delayed in trauma patients
with compromised renal function [18].
Like many other pharmacologic studies, these ndings are also sex-
biased and only reect male physiology. Human pharmacokinetic TXA
data have only been reported in young adult men [17-19].
Anatomical differences must also be considered. Tibial IO pharmaco-
kinetics in immature swine may differ from a humeral or sternal site in
adult humans. Humeral and sternal circulations are closer to central ve-
nous circulation, and the sternal marrow compartment has a smaller
volume compared to a long bone [36]. The IO TXA in this study was
also injected into red marrow. Adult long bones contain almost exclu-
sively yellow marrow after 20 years of age [36]. Yellow marrow has a
different vascular structure but appears equally capable of delivering
IO administered agents into the circulation.
Finally, the proximity of the auricular venous circulation to the jug-
ular sampling site created a potential sampling artifact and may have
skewed the Cmax results. IO tranexamic acid Cmax and Tmax are potential-
ly more equivalent to the IV route than this study demonstrated.
5. Conclusion
Although TXA is currently being administered intraosseously, there
was no experimental evidence prior to this study to show that IO ad-
ministration is pharmacologically and physiologically equivalent to IV
administration. Results from this swine model support the pharmacoki-
netic bioequivalence of IO and IV administration of TXA. The availability
of pharmacokinetic comparisons in an animal model is the rst step in
developing evidence-based protocols.
Competing Interests
The authors declare that they have no conicts of interest.
Acknowledgments
Cheryl Meek, Lindsay Burrowes, John Tyberg, Kendal Weatherby,
Anukul Ghimire.
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