Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery

Gertler, Ralph; Gruber, Michael; Grassin-Delyle, Stanislas; Urien, Saı̈k; Martin, Klaus; Tassani-Prell, Peter; Braun, Siegmund; Burg, Simon; Wiesner, Gunther

doi:10.1111/bcp.13274

Cited by 22 publications

(18 citation statements)

References 37 publications

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“…Dosing simulation supported a CXM regimen of 25 mg kg À1 as a primary bolus and into the CPB prime and a 5 mg kg À1 h À1 infusion throughout the perioperative course to maintain CXM concentrations above 32 mg l À1 . These PK parameters are in agreement with previously published findings in the same cohort with tranexamic acid [13]. With respect to cefuroxime in paediatrics, the only data published were obtained in older children and results were comparable to those of the present study (according to values presented in the abstract, which are much more physiologically relevant than those in the manuscript's main body) [8].…”

Section: Discussionsupporting

confidence: 93%

Pharmacokinetics of cefuroxime in infants and neonates undergoing cardiac surgery

Gertler

Gruber

Wiesner

et al. 2018

Brit J Clinical Pharma

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Section: Discussionsupporting

confidence: 93%

Pharmacokinetics of cefuroxime in infants and neonates undergoing cardiac surgery

Gertler

Gruber

Wiesner

et al. 2018

Brit J Clinical Pharma

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“…The parameter estimates are in the range of the values described in previous population models, with a clearance in the range 2.45–7.4 l.h −1 and an apparent volume of distribution between 16.5 l and 46.3 l for a 70 kg individual .…”

Section: Discussionmentioning

confidence: 58%

“…This is, to our knowledge, the first study to examine the plasma levels and pharmacokinetics of tranexamic acid in patients with severe trauma who had received pre‐hospital tranexamic acid. The pharmacokinetics of tranexamic acid have previously been described mainly during cardiac surgery, and the data also fitted a two‐compartment model . The allometric adjustment of volumes and clearances explained a significant part of the between‐subject variability.…”

Section: Discussionmentioning

confidence: 98%

“…Tranexamic acid pharmacokinetics have previously been described mainly in cardiac surgery , and the doses used in trauma in both large‐scale in‐hospital and pre‐hospital trials were purely empirical, in the absence of pharmacokinetic studies. Hence, data on blood tranexamic acid concentrations and pharmacokinetics in trauma patients are lacking, and may be of great value in improving the dosing regimen and the risk/benefit ratio for administration.…”

Section: Introductionmentioning

confidence: 99%

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Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis

et al. 2018

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Tranexamic acid is used both pre-hospital and in-hospital as an antifibrinolytic drug to treat or prevent hyperfibrinolysis in trauma patients; dosing, however, remains empirical. We aimed to measure plasma levels of tranexamic acid in patients receiving pre-hospital anti-hyperfibrinolytic therapy and to build a population pharmacokinetic model to propose an optimised dosing regimen. Seventy-three trauma patients were enrolled and each received tranexamic acid 1 g intravenously pre-hospital. A blood sample was drawn after arrival in the emergency department, and we measured the plasma tranexamic acid concentration using liquid chromatography-mass spectrometry, and modelled the data using non-linear mixed effect modelling. Tranexamic acid was administered at a median (IQR [range]) time of 43 (30-55 [5-135]) min after trauma. Plasma tranexamic acid levels were determined on arrival at hospital, 57 (43-70 [20-148]) min after pre-hospital administration of the drug. The measured concentration was 28.7 (21.5-38.5 [8.7-89.0]) μg.ml . Our subjects had sustained severe trauma; injury severity score 20 (16-29 [5-75]), including penetrating injury in 2.8% and isolated traumatic brain injury in 19.7%. The pharmacokinetics were ascribed a two-compartment open model with body-weight as the main covariate. As tranexamic acid concentrations may fall below therapeutic levels during initial hospital treatment, we propose additional dosing schemes to maintain a specific target blood concentration for as long as required. This is the first study to investigate plasma level and pharmacokinetics of tranexamic acid after pre-hospital administration in trauma patients. Our proposed dosing regimen could be used in subsequent clinical trials to better study efficacy and tolerance profiles with controlled blood concentrations.

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“…The gap in our understanding of the pharmacokinetics of lysine analogs in neonates and children has been partially filled by the publication of a few pharmacokinetic studies. [22][23][24][25][26] The first pharmacokinetic study was published by Ririe et al in 2002. 22 In that study, the authors determined the PK of EACA in eight children who underwent surgical repair of congenital heart defects.…”

Section: Efficacy and Safety Of Antifibrinolytic Agentsmentioning

confidence: 99%

Use of antifibrinolytics in pediatric cardiac surgery: Where are we now?

Faraoni

Rahe

CyBulski

2018

Pediatric Anesthesia

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Summary Fibrinolytic activation is a major and preventable source of bleeding in neonates and children undergoing cardiac surgery with cardiopulmonary bypass. Based on the existing literature (adult and pediatric; cardiac and noncardiac), prophylactic administration of antifibrinolytic agents can help reduce fibrinolytic activation, and consequently reduces perioperative bleeding and the requirement for blood product transfusion. Due to the increased risk of renal failure and mortality reported in adults undergoing cardiac surgery, aprotinin should not be considered as a safe option in neonates and children. Further well‐designed studies would be required before the prophylactic administration of aprotinin could be considered in pediatric cardiac surgery. The lysine analogs, tranexamic acid and ϵ‐aminocaproic acid,, should be considered as safe and effective antifibrinolytic agents. Although no major side effects have been reported following the administration of lysine analogs in children undergoing cardiac surgery, high‐dose tranexamic acid should not be recommended in order to avoid the increased risk of clinical seizures. Despite the recent advances made in our understanding of the pharmacokinetics of tranexamic acid and ϵ‐aminocaproic acid,, the optimal plasmatic concentration to be targeted remains unknown. Further studies are therefore urgently needed to better define the optimal dose regimen to be used in neonates and children. In the meantime, the dose regimen published in the most recent pharmacokinetic studies can be used. Although no studies have assessed the effect of massive bleeding and transfusion on the plasmatic concentrations of the lysine analogs, additional boluses might be considered in the presence of bleeding and/or when signs of fibrinolytic activations are observed on viscoelastic hemostatic assays.

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Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery

Abstract: The introduction of a modified dosing regimen using a starting bolus followed by an infusion and a CPB prime bolus would prohibit the potential risk of seizures caused by high peak concentrations and also maintain therapeutic plasma concentration above 20 μg ml .

Cited by 22 publications

References 37 publications

Pharmacokinetics of cefuroxime in infants and neonates undergoing cardiac surgery

Pharmacokinetics of cefuroxime in infants and neonates undergoing cardiac surgery

Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis

Use of antifibrinolytics in pediatric cardiac surgery: Where are we now?

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