The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model

Derickson, Michael; McClellan, John M.; Marko, Shannon T.; Kuckelman, John; Phillips, Cody; Barron, Morgan R.; Martin, Matthew J.; Loughren, Michael

doi:10.1097/ta.0000000000001861

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…route, although TXA losses to haemorrhage may have resulted in some timedependant changes in pharmacokinetic parameters and underestimation of bioavailability. 22 Although we attempted to obtain a blood sample 10 min after the i.v. injection, because patient care was the priority, in many cases this was not possible.…”

Section: Strengths and Weaknessesmentioning

confidence: 99%

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial

Grassin-Delyle

Shakur-Still

Picetti

et al. 2021

British Journal of Anaesthesia

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Background: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. Methods: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0$5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixedeffect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. Results: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h À1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h À1 for elimination clearance, 11.7 L h À1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L À1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. Conclusions: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. Clinical trial registration: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).

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Section: Strengths and Weaknessesmentioning

confidence: 99%

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial

Grassin-Delyle

Shakur-Still

Picetti

et al. 2021

British Journal of Anaesthesia

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“…4,47 This study was limited by the small sample size used, although smaller sample sizes are common in swine studies. 25,26 Female pigs have increased survival during hemorrhage, 48 which may have impacted outcomes in all groups. Using male pigs in future experiments may be translationally important given that human trauma victims are predominantly male in both the military 49 and among civilians.…”

Section: Discussionmentioning

confidence: 99%

“…This study was limited by the small sample size used, although smaller sample sizes are common in swine studies 25,26 . Female pigs have increased survival during hemorrhage, 48 which may have impacted outcomes in all groups.…”

Section: Discussionmentioning

confidence: 99%

“…Animals were allowed to bleed freely into the abdomen for 2 minutes before the laparotomy was rapidly closed with sutures. Then, 1 g of TXA (~25 mg/kg) was infused intravenously, as reported in other swine models of hemorrhage 25,26 . Animals were randomized using a coin toss to receive either SPTP and fluid resuscitation (SPTP group) or fluid resuscitation alone (controls) (n = 5 per group).…”

Section: Methodsmentioning

confidence: 99%

“…Then, 1 g of TXA (~25 mg/kg) was infused intravenously, as reported in other swine models of hemorrhage. 25,26 Animals were randomized using a coin toss to receive either SPTP and fluid resuscitation (SPTP group) or fluid resuscitation alone (controls) (n = 5 per group). The control group receiving intravenous fluid resuscitation was intended to model aspects of real-world management of prehospital NCTH.…”

Section: Surgery For Closed-abdomen Bleeding Model and Survival Studymentioning

confidence: 99%

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Percutaneous delivery of self-propelling thrombin-containing powder increases survival from noncompressible truncal hemorrhage in a swine model of coagulopathy and hypothermia

Cau

Ali-Mohamad

Yeh

et al. 2022

J Trauma Acute Care Surg

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BACKGROUND: Noncompressible truncal hemorrhage (NCTH) remains a leading cause of preventable death on the battlefield. Definitively managing severe NCTH requires surgery within the first hour after injury, which is difficult when evacuating casualties from remote and austere environments. During delays to surgery, hemostatic interventions that are performed prehospital can prevent coagulopathy and hemorrhagic shock and increase the likelihood that casualties survive to receive definitive care. We previously reported that a self-propelling thrombin-containing powder (SPTP) can be delivered percutaneously into the abdomen as a minimally invasive intervention and can self-disperse through pooled blood to deliver the hemostatic agents thrombin and tranexamic acid locally to noncompressible intracavitary wounds. We hypothesized that, in swine with massive NCTH, dilutional coagulopathy, and hypothermia, delivering SPTP could extend survival times. METHODS:Ten swine (n = 5 per group) underwent NCTH from a Grade V liver injury following a midline laparotomy. The laparotomy was closed with sutures afterwards, creating a hemoperitoneum, and animals were managed with crystalloid fluid resuscitation, or crystalloid resuscitation and SPTP. Self-propelling thrombin-containing powder was delivered into the closed abdomen using a CO 2 -powered spray device and a catheter placed into the hemoperitoneum, entering through the upper right quadrant using the Seldinger technique. Survival to 1 and 3 hours was recorded. In an additional animal, hemorrhage was created laparoscopically, and SPTP was imaged in situ within the abdomen to visually track dispersion of the particles. RESULTS:Self-propelling thrombin-containing powder dispersed as far as 35 ± 5.0 cm within the abdomen. It increased survival to 1 and 3 hours (Kaplan-Meier p = 0.007 for both). The median survival time was 61 minutes with SPTP and 31 minutes without ( p = 0.016). CONCLUSION: Self-propelling thrombin-containing powder effectively disperses medications throughout a hemoperitoneum and increases survival in a model of NCTH. It is a promising strategy for nonsurgical management of NCTH, warranting further testing of its safety and efficacy.

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Percutaneous delivery of self-propelling hemostatic powder for managing non-compressible abdominal hemorrhage: a proof-of-concept study in swine

Cau¹,

Ali-Mohamad²,

Baylis³

et al. 2022

Injury

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The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model

Abstract: Therapeutic, level II.

Cited by 6 publications

References 20 publications

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial

Percutaneous delivery of self-propelling thrombin-containing powder increases survival from noncompressible truncal hemorrhage in a swine model of coagulopathy and hypothermia

Percutaneous delivery of self-propelling hemostatic powder for managing non-compressible abdominal hemorrhage: a proof-of-concept study in swine

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