Injury remains a leading cause of death throughout the world, and hemorrhage is the most common cause of preventable death in injured patients (1–5). Efforts to prevent hemorrhage-related mortality focus on bleeding control with tourniquets and hemostatic dressings, rapid transport to trauma centers, balanced resuscitation, and correction of trauma-induced coagulopathy (TIC) (3, 6). Despite concentrated research efforts, few adjuncts exist to combat TIC. Tranexamic acid (TXA) is the only medication found in a randomized controlled trial to improve survival in patients with traumatic hemorrhage (4, 7, 8). TXA is an antifibrinolytic medication which inhibits plasminogen. This inhibition prevents the degradation of fibrin and thereby stabilizes clot by preventing clot lysis (9, 10). The current standard TXA dose for trauma patients is based on the CRASH-2 trial, which extrapolated this dose from other indications. The protocol includes a 1 g intravenous (IV) infusion over 10 min, followed by a second 1 g infusion over 8 h (7, 9). In the CRASH-2 trial this dose improved survival, but the timing of TXA administration was critical, as evidenced by an increased risk of death if given after 3 h (7). Even a delay of minutes within the first 3 h after injury has been shown to reduce the benefit of TXA (11). Current dosing requires dedicated IV access, as TXA is not compatible with blood products or penicillin (9). Obtaining IV access for TXA administration in a hypotensive patient can be a challenge, particularly in austere environments, thereby delaying or preventing its administration.
Potential alternative routes for TXA administration have been discussed, and promising work has been done to show the possibility of intraosseous (IO) administration. This work has revealed that there is a difference in maximum concentration (Cmax) between IV and IO forms of TXA during the IV infusion in normotensive swine (12). Administration of TXA via these two routes in pigs in hypovolemic shock resulted in similar pharmacokinetics and equivalent correction of hyperfibrinolysis (13). While IO administration appears to be a reasonable and more rapid alternative to IV (12, 13), the dedicated IO line would still be monopolized by TXA infusion and not be available for transfusion. Alternatively, an intramuscular (IM) injection of TXA would allow for even more rapid early administration without limiting access for resuscitation. Because of this, the United States Military Special Forces has specifically called for possible IM administration of TXA (14). However, it remains unknown whether IM injection results in serum TXA concentrations similar to IV infusion in the setting of continued hemorrhage and hypotension when the distribution of blood flow to the skeletal muscle is altered (15).
We hypothesized that in a swine model of ongoing hemorrhage, IM TXA would generate equivalent serum concentrations and ability to inhibit in vitro hyperfibrinolysis when compared with IV TXA.
The Institutional Animal Care and Use Committee at David Grant Medical Center, Travis Air Force Base, California approved this study. All animal care and use were in strict compliance with the Guide for the Care and Use of Laboratory Animals in a facility accredited by AAALAC International. Twelve healthy adult, castrate male, and non-pregnant female Yorkshire-cross swine (Sus scrofa; University of California, Davis) arrived together and were acclimated for a minimum of 7 days prior to use. All animals were pair-housed indoors at a consistent temperature of 20 ± 2oC and 66 ± 1% humidity with a 12–12 light–dark cycle. These parameters were controlled by a dedicated system engineered and maintained to meet Institute of Laboratory Animal Resources Guide recommendations. They were provided visual, olfactory, and when possible, tactile contact with conspecifics to provide social interaction and enrichment. They were fed a commercial swine diet (Teklad #7037; Envigo, Indianapolis, Ind) twice daily, and their health status was closely monitored. At the time of experimentation, animals weighed 57.5 kg on average (range 49 kg–67 kg) and were between 3 and 5 mo of age. This weight range reflects baseline differences on arrival as well as rapid growth while the experiments were conducted.
An overview of the protocol, including animal preparation, intervention, and critical care, is presented in Figure 1. After 8 to 10 h of fasting, during which time they had free access to water, animals were premedicated with 6.6 mg/kg intramuscular tiletamine/zolazepam (Telazol; Zoetis, Inc, Kalamazoo, Mich). Following 5% isoflurane induction and endotracheal intubation, general anesthesia was maintained with 2% isoflurane in 100% oxygen. Animals were mechanically ventilated with tidal volumes of 6 mL/kg to 10 mL/kg and a respiratory rate of 10 to 15 breaths per min, sufficient to maintain end tidal CO2 at 40 ± 5 mm Hg, which was measured through a side-stream capnometer built into the anesthesia machine. To ensure a deep surgical anesthetic plane throughout the entirety of the experiment, heart rate and blood pressure were continuously monitored, and jaw tone, eye position, and palpebral reflex were assessed every 10 min.
The spleen was removed via laparotomy to minimize hemodynamic variation from autotransfusion in this controlled hemorrhage model (16). Balanced electrolyte solution (Plasma-Lyte A; Baxter Healthcare Corporation, Deerfield, Ill) was administered to overcome insensible losses at 10 mL/kg per hour until the abdomen was closed and then decreased to 5 mL/kg per hour for the remainder of the study. An underbody warmer was used to maintain core body temperature between 35°C and 37°C. Bilateral 7 Fr femoral arterial sheaths were placed percutaneously using ultrasound guidance for controlled hemorrhage and blood sampling. A 9 Fr dual lumen catheter was placed percutaneously into the right external jugular vein for medication administration and resuscitation. A 5 Fr carotid arterial catheter was placed via cut-down for ongoing blood pressure monitoring. A target mean arterial pressure (MAP) of 65 mm Hg or greater was achieved via use of 10 mL/kg Plasma-Lyte A boluses and an IV infusion of norepinephrine (0.01 μg/kg per minute) titrated to ensure prehemorrhage euvolemia and to offset the vasodilatory effects of general anesthesia, respectively.
Twelve swine underwent controlled hemorrhage of 15% blood volume over 15 min. Hemorrhage was then paused, and randomization was performed by a veterinary technician choosing a randomization sheet from an opaque envelope. The surgeons were therefore unaware of the ultimate study group at the time of the surgical preparation. The animals were randomized to receive 1 g IV TXA (X-Gen Pharmaceuticals, Horseheads, NY) given over 10 min (n = 5), 1 g IM TXA (n = 5), or 10 mL of IM normal saline as a placebo (n = 2). The IM injections were administered as two 5 mL boluses in both thighs in the semitendonosus/semimembranosus muscle complex 4 cm distal to the ischial tuberosity. No muscle massage was performed after IM injection. Immediately following the administration of TXA or normal saline, hemorrhage was resumed to complete an additional controlled hemorrhage of 20% blood volume over 45 min. Hemorrhage volume was calculated based on the animal's weight and assumption of a total blood volume of 66 mL/kg [35% hemorrhage volume = weight (kg) × 66 × 0.35]. The rate of hemorrhage was titrated to maintain a MAP above 40 mm Hg while still ensuring completion within the allotted time. Two animals were randomized to the placebo group to validate the model and assess the animals’ coagulation profile on ROTEM independent of TXA.
At the end of the 35% total blood volume hemorrhage, the animals were resuscitated with 10 mL/kg Plasma-Lyte A and 10 mL/kg of previously shed blood that did not contain any TXA. The animals then entered the critical care phase of the experiment and were monitored for 4 h. Titrated norepinephrine infusion and 10 mL/kg Plasma-Lyte A boluses were used to maintain a MAP above 40 mm Hg. Serum glucose concentrations less than 60 mg/dL were corrected with 50% dextrose IV boluses and continuous infusions (0 mL to 109 mL per animal). Serum calcium concentrations less than 1.00 mmol/L were corrected with 23% IV calcium gluconate, which was also administered to every animal upon transfusion of whole blood to off-set the citrate within the blood bag (7 mL calcium gluconate per 450 mL whole blood; 8.4 mL to 10.3 mL per animal). All animals were euthanized at the conclusion of the study with an IV injection of 390 mg/mL pentobarbital given as a 1 mL/5 kg IV infusion.
Physiologic data, to include heart rate, mean arterial pressure, temperature, and peripheral capillary oxygen saturation, were collected at millisecond intervals throughout the experiment using an anesthesia information management system (Philips IntelliVue MP50 Patient Monitor; Pacific Medical Co; San Celemente, Calif). Blood samples were obtained just prior to hemorrhage and then at 0, 5, 10, 15, 22.5, 30, 45, and 60 min following TXA administration and hourly thereafter. Serum collected at these time points was stored at −80°C until later analyzed to determine TXA concentration. Excluding the 5, 10, 15, and 30 time points, all others involved blood draws for complete blood counts, coagulation parameters (international normalised ratio, partial thromboplastin time, fibrinogen), arterial blood gas, and thromboelastometric analysis. Total blood volume drawn for laboratory analysis was 146 mL per animal and was not included in the total hemorrhage volume, which was approximately 1,135 mL to 1,541 mL per animal.
Determination of TXA concentrations
TXA concentrations in serum samples were quantified by liquid chromatography-mass spectrometry (LC-MS). Individual, non-pooled, specimens were prepared by adding 200 μL serum to 200 μL of 2.5% perchloric acid and 3 μL of 0.5 μg/mL cis-4 aminocyclohexanecarboxylic acid as the internal standard. These were then vortexed and centrifuged for 10 min at 14,000 rpm. The supernatant was added to LC-MS sample vials containing 150 μL of 0.1 M sodium hydroxide and mixed. Calibration standards and controls were prepared by spiking blank pig serum with known amounts of TXA. The LC-MS system—a 1,290 Infinity HPLC coupled to a 6,550 ifunnel Q-TOF mass spectrometer (Agilent Technologies Inc, Santa Clara, Calif)—was injected with 0.04 μL of sample. The mobile phase consisted of 99% formic acid in water (0.1% w/w—solvent A) and 1% methanol (solvent B). Separation was achieved using an Agilent Technologies ZORBAX Eclipse Plus C18 Rapid Resolution HD column (2.1 mm × 50 mm × 1.8 μm) maintained at 28°C. The mass spectrometer was operated in the positive ion mode and monitored at m/z, amu 158.12 for TXA and 144.10 for the internal standard.
We assessed the functional activity of TXA in citrated whole blood samples using rotational thromboelastometry (ROTEM delta, Instrumentation Laboratory, Bedford, Mass) on serum spiked with recombinant tissue plasminogen activator (tPA; ALTEPLASE, Genentech, South San Francisco, Calif) using methods similar to those reported by others (15–18). Briefly, recombinant tPA was reconstituted to provide 3 μg/mL final concentration in the ROTEM EXTEM assay, which was run according to the manufacturer's instructions until a lysis index after 30 min (LI30) was obtained.
Data were assessed for skewness and kurtosis and presented as mean ± standard deviation or median [interquartile range], as appropriate. Hypotheses were tested using either t tests or Wilcoxon rank-sum tests, depending on distribution. Pharmacokinetic parameters including: maximum serum TXA concentration, Cmax; time to maximum concentration, Tmax; elimination rate constant, Ke; half-life, t1/2; and area under the curve by the trapezoidal method, (AUC) were calculated for each individual using standard formulas assuming a non-compartmental model and summarized. With time treated as a categorical variable, due to the discrete time-points tested, two-factor repeated measures analysis of variance was used to assess the effects of treatment (IV vs. IM), time-point, and treatment X time interaction. Pairwise comparisons were conducted using Dunnett method with IV TXA concentration at time point 0 as the control.
All statistical analyses were performed using a commercial software package (STATA version 15.1; Stata Corp, College Station, Tex). Statistical significance was set at P < 0.05. Using data from a previous experiment in our laboratory, which compared the mean TXA concentration between animals receiving the drug via IV or IM injection at 30-min post-administration, we estimated an average effect size of 2 to detect a difference in concentration. We therefore calculated that a sample size of five animals per group would yield 80% statistical power, given an alpha of 0.05. This calculation was performed for two samples, as the IV and IM groups were used to assess the primary outcome, and the placebo group was not.
Baseline physiologic and biochemical parameters of the animals in the IV and IM groups are shown in Table 1. Following controlled hemorrhage, all animals achieved class III shock as evidenced by: the volume of blood loss (35% of total blood volume), significant elevations in heart rate (IV group 86 [85–102] vs. 151 [149–189] bpm, P = 0.01, and IM group 87 [80–90] vs. 141 [134–176 bpm, P = 0.05, at baseline and after hemorrhage, respectively), and markedly decreased MAP (IV group 75 [71–89] vs. 61 [57–71] mm Hg, P = 0.06, and IM group 73 [68–85] vs. 52 [43–52] mm Hg, P = 0.01, at baseline and after hemorrhage, respectively) (Tables 1 and 2). All animals survived to the end of the study. All values reported herein are medians with corresponding IQR.
Serum TXA concentrations over time and pharmacokinetic data are shown in Figure 2 and Table 3, respectively. The results of two-factor repeated measures analysis of variance indicated a significant interaction between treatment and time (F10,88 = 4.99, P = 0.053), as expected. With the TXA concentration of the IV group just prior to administration (time 0) as the control, all IV TXA concentrations were significantly (P < 0.05) greater than control except at time 240 (P = 0.42) and time 300 (P = 0.84). Similarly, all IM TXA concentrations were significantly (P < 0.05) greater than control except at time 240 (P = 0.31) and time 300 (P = 0.80). Maximum drug concentrations were significantly higher in animals receiving IV versus IM TXA (IV 100 [93–106] and IM 63 [59–71] μg/mL, P = 0.02) during the 10-min infusion. However, the serum concentrations were not statistically different by 15 min (IV 64 [59–76] and IM 59 [58–61] μg/mL, P = 0.47).
The time to maximum concentration was also not significantly different between the IV and IM routes (IV 5 [5–10] and IM 10 [10–15] min, P 0.12). Of note, there was an outlier within the IM group, which had a much slower absorption time with Tmax occurring at T45. There was also no difference in the concentration–time AUC between TXA given by the IV and IM routes (IV 9,798 [8,130–11,257] μg-min/mL and IM 9,544 [8,859–10,434] μg-min/mL, P = 0.60). The absolute bioavailability of IM TXA was 97%.
Coagulation metrics (platelet counts, fibrinogen concentrations, prothrombin times) and ROTEM measurement of clot formation speed and quality (CT, CFT, MCF) were not significantly different between the two routes of administration at baseline (Table 1) or at the end of the study (Table 2). In vitro addition of tPA to serum successfully induced hyperfibrinolysis in all samples, as determined by an increase in maximum lysis and a reduction in the percentage of clot stability remaining (LI30) at baseline (Table 4 and Fig. 3A, Supplemental Material, Supplemental Digital Content, http://links.lww.com/SHK/A926). Administration of TXA stabilized clot and reversed hyperfibrinolysis on ROTEM analysis equally between the groups (Table 4 and Fig. 3B).
To our knowledge, this is the first demonstration of IM TXA pharmacokinetics in the setting of class III hemorrhagic shock. Our findings indicate that IV and IM administration of identical doses of TXA result in similar total body drug exposure even in the shock state. The IV route did result in a higher peak TXA concentration immediately after administration, but this difference was seen only during active IV infusion. This difference in Cmax during the IV infusion was also observed with IO administration of TXA (12). Although hypovolemia is thought to cause shunting of blood flow away from skeletal muscle, this does not appear to affect the overall bioavailability of TXA in pigs. Importantly, both routes of administration were equally effective at correcting tPA-induced in vitro hyperfibrinolysis.
Prior studies have identified the therapeutic concentration of TXA required to reverse hyperfibrinolysis in an in vitro model of tPA-induced hyperfibrinolysis (17–19). These works have shown that the therapeutic level of TXA in humans is 11.4μg/mL to 14.7 μg/mL (17, 18). Both IV and IM routes of administration in our study achieved this level throughout the entirety of the experiment. In fact, all 10 animals achieved this level by 5 min, the first measured time point after administration. Both routes were equally effective at correcting in vitro hyperfibrinolysis on ROTEM and had corrected the LI30 by the first time point after administration. Therefore, the clinical significance of the difference in peak concentration is unclear, and the higher peak concentrations with IV administration may provide no further clinical benefit.
The timing of TXA administration is critical. Prior research has demonstrated that TXA improves survival within the first 3 h after injury (7, 8) and that this survival benefit decreases by 10% with every 15 min delay in its administration (11). After 3 h, mortality increases (7). In this study, there was no significant difference in time to maximum concentration between the IV and IM routes, but there was a trend toward more rapid peak concentration in the IV group, as well as one outlier in the IM group with a significantly prolonged Tmax. This raises the concern that with a larger sample size, we may have observed a significant difference in the time to maximum concentration. This might be expected given that the IV TXA is being administered directly into the vasculature, while the IM TXA has an absorption phase. Multiple medications have demonstrated prolonged time to peak concentrations when given via the IM route in both animal and human studies. For example, glucagon has an increased time to peak concentration but no difference in efficacy when given IM versus IV (20). IM administration of both atropine and pralidoxime results in slower absorption but similar AUC (15, 21, 22), with exacerbation of the absorption time by hypovolemia in swine (15, 21). Conversely, both fentanyl and propofol have increased peak concentrations, and therefore potency, during hemorrhagic shock when administered via the IM route which has been attributed to reduced clearance (23, 24). A small study performed in three healthy euvolemic human volunteers showed equal bioavailability of 500 mg IM and IV TXA (25), but time to peak concentration was not compared. Ultimately, there is no evidence that IM TXA has a long absorption phase, even in the setting of hemorrhagic shock. Furthermore, although the Tmax could be different, all 10 animals achieved the estimated therapeutic concentration by 5 min.
In a massively injured patient, obtaining multiple IV or even IO access points for separate delivery of blood products and TXA infusion could take several minutes, thereby delaying one of these crucial interventions. IM injection could be nearly immediate. Therefore, any potential prolonged time to Cmax by the IM route of administration of TXA may be mitigated by the faster administration of IM TXA in clinical practice.
Our findings suggest that IM TXA administration could be as efficacious as IV administration in the setting of hemorrhagic shock. This is particularly applicable for the military, where initial trauma care is occurring in austere environments, and IV or IO access is often limited. A combat medic could inject the medication into the patient's thigh upon arrival to the scene, thereby increasing the likelihood that administration would be performed within the 3-h window. Furthermore, an auto-injector would allow the wounded warrior to self-administer the medication at the onset of massive hemorrhage prior to response by a combat medic. Once IV or IO access is achieved, these routes can be used for resuscitation with blood products rather than for infusion of the initial bolus of TXA. In the civilian setting, paramedics could use a TXA auto-injector in the field or during transport, thereby focusing their time and IV access on resuscitation and overall care of the massively injured patient.
There are several limitations to this study. First, the number of animals in each group was small but was based on an a priori sample size calculation with the goal of reduction of animal use. This could have resulted in a failure to detect a difference in Tmax, as previously discussed. Second, coagulation profiles between humans and swine are inherently different with swine being, in general, more hypercoagulable but similar with regards to fibrinolysis (26). These differences could cause the ROTEM analysis of initial clotting features to be skewed by the animals’ inherent hypercoagulability, but it is less likely for this inter-species difference to have an effect on fibrinolysis. Furthermore, ROTEM was not used in this study to assess the coagulation profile of the animals. Rather, it was used to assess the functional ability of the in vivo TXA, at whichever concentration it had achieved, to correct in vitro hyperfibrinolysis. Third, TXA was administered as a single bolus, rather than a bolus followed by a slow infusion, as is the current practice regimen. This was done to compare equal doses of TXA given by both routes from a pharmacokinetic standpoint. Finally, the hemorrhage was performed via a femoral arterial catheter in a controlled fashion. This minimized experimental variability, but it did not allow for the analysis of efficacy of the drug at forming clot in vivo and potentially affecting blood loss and survival time. Because of this, the clinical significance of the difference in Cmax and Tmax between the IV and IM forms cannot be determined based on this study. These limitations notwithstanding, this study demonstrates that total body exposure to IM and IV TXA is similar, even in the setting of hemorrhagic shock.
Investigation is needed to determine the significance of the diminished Cmax of the IM form of TXA. Derickson et al. (27) demonstrated that 25% of IV TXA was lost via hemorrhage in a swine model. In our study the IV and IM TXA concentrations were equivalent at 15 min, and thus it is possible that the drug was lost in the hemorrhaged blood and thereby did not contribute to a difference in overall effectiveness. Because both IV and IM TXA resulted in the successful reversal of in vitro hyperfibrinolysis, even at lower than peak concentrations, one can infer that the excess drug within the blood of the pigs that received IV TXA was inconsequential. However, this cannot be determined based on this controlled hemorrhage model. An uncontrolled hemorrhage model is required to determine if the excess available drug (higher Cmax) at an earlier time point after administration (shorter Tmax) would be critical for stabilizing clot and attenuating blood loss during the infusion period. Beyond the need for an uncontrolled hemorrhage animal model, a human study is needed to definitively determine noninferiority with regards to overall survival and potential benefit of more rapid administration of IM TXA as compared with the current IV TXA dosage in massive hemorrhage.
The pharmacokinetics of IM TXA were similar to IV TXA during class III hemorrhagic shock in our swine model, with a bioavailability of 97% for IM administration. IV administration resulted in a higher serum concentration only during the infusion period. All concentrations remained above levels previously reported to correct tPA-induced in vitro hyperfibrinolysis in human plasma and were successful at doing the same in the hypovolemic swine. IM TXA may prove beneficial in scenarios where difficulty establishing dedicated IV access could otherwise limit or delay its use, but further studies are required to determine equivalence of clinical efficacy.
The authors thank Mr Carl Gibbons for assistance performing lab analyses and Mr Nolan Hudson for determining TXA concentrations. The authors also thank the entire Clinical Investigations Facility at David Grant Medical Center for their exquisite care of the animals and assistance with procedures and laboratory analyses.
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