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      Different dose regimes and administration methods of tranexamic acid in cardiac surgery: a meta-analysis of randomized trials

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          Abstract

          Background

          The efficacy of tranexamic acid (TXA) to reduce perioperative blood loss and allogeneic blood transfusion in cardiac surgeries has been proved in previous studies, but its adverse effects especially seizure has always been a problem of concern. This meta-analysis aims to provide information on the optimal dosage and delivery method which is effective with the least adverse outcomes.

          Methods

          We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE for all relevant articles published before 2018/12/31. Inclusion criteria were adult patients undergoing elective heart surgeries, and only randomized control trials comparing TXA with placebo were considered. Two authors independently assessed trial quality and extracted relevant data.

          Results

          We included 49 studies with 10,591 patients into analysis. TXA significantly reduced transfusion rate (RR 0.71, 95% CI 0.65 to 0.78, P<0.00001). The overall transfusion rate was 35%(1573/4477) for patients using TXA and 49%(2190/4408) for patients in the control group. Peri-operative blood loss (MD − 246.98 ml, 95% CI − 287.89 to − 206.06 ml, P<0.00001) and re-operation rate (RR 0.62, 95% CI 0.49 to 0.79, P<0.0001) were also reduced significantly. TXA usage did not increase risk of mortality, myocardial infarction, stroke, pulmonary embolism and renal dysfunction, but was associated with a significantly increase in seizure attack (RR 3.21, 95% CI 1.04 to 9.90, P = 0.04).The overall rate of seizure attack was 0.62%(21/3378) for patients using TXA and 0.15%(5/3406) for patients in the control group.

          In subgroup analysis, TXA was effective for both on-pump and off-pump surgeries. Topical application didn’t reduce the need for transfusion requirement, while intravenous delivery no matter as bolus injection alone or bolus plus continuous infusion were effective. Intravenous high-dose TXA didn’t further decrease transfusion rate compared with low-dose regimen, and increased the risk of seizure by 4.83 times. No patients in the low-dose group had seizure attack.

          Conclusions

          TXA was effective in reducing transfusion requirement in all kinds of cardiac surgeries. Low-dose intravenous infusion was the most preferable delivery method which was as effective as high-dose regimen in reducing transfusion rate without increasing the risk of seizure.

          Electronic supplementary material

          The online version of this article (10.1186/s12871-019-0772-0) contains supplementary material, which is available to authorized users.

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          Most cited references64

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          High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients.

          In 2 separate centers, we observed a notable increase in the incidence of postoperative convulsive seizures from 1.3% to 3.8% in patients having undergone major cardiac surgical procedures. These events were temporally coincident with the initial use of high-dose tranexamic acid (TXA) therapy after withdrawal of aprotinin from general clinical usage. The purpose of this review was to perform a retrospective analysis to examine whether there was a relation between TXA usage and seizures after cardiac surgery. An in-depth chart review was undertaken in all 24 patients who developed perioperative seizures. Electroencephalographic activity was recorded in 11 of these patients, and all patients had a formal neurological evaluation and brain imaging studies. Twenty-one of the 24 patients did not have evidence of new cerebral ischemic injury, but seizures were likely due to ischemic brain injury in 3 patients. All patients with seizures did not have permanent neurological abnormalities. All 24 patients with seizures received high doses of TXA intraoperatively ranging from 61 to 259 mg/kg, had a mean age of 69.9 years, and 21 of 24 had undergone open chamber rather than coronary bypass procedures. All but one patient were managed using cardiopulmonary bypass. No evidence of brain ischemic, metabolic, or hyperthermia-induced causes for their seizures was apparent. Our results suggest that use of high-dose TXA in older patients in conjunction with cardiopulmonary bypass and open-chamber cardiac surgery is associated with clinical seizures in susceptible patients.
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            Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA.

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              Pharmacokinetics of tranexamic acid during cardiopulmonary bypass.

              Tranexamic acid (TA) reduces blood loss and blood transfusion during heart surgery with cardiopulmonary bypass (CPB). TA dosing has been empiric because only limited pharmacokinetic studies have been reported, and CPB effects have not been characterized. We hypothesized that many of the published TA dosing techniques would prove, with pharmacokinetic modeling and simulation, to yield unstable TA concentrations. Thirty adult patients undergoing elective coronary artery bypass grafting, valve surgery, or repair of atrial septal defect received after induction of anesthesia: TA 50 mg/kg (n = 11), TA 100 mg/kg (n = 10), or TA 10 mg/kg (n = 10) over 15 min, with 1 mg x kg(-1) x hr(-1) maintenance infusion for 10 h. TA was measured in plasma using high performance liquid chromatography. Pharmacokinetic modeling was accomplished using a mixed effects technique. Models of increasing complexity were compared using Schwarz-Bayesian Criterion (SBC). Tranexamic acid concentrations rapidly fell in all three groups. Data were well fit to a 2-compartment model, and adjustments for CPB were supported by SBC. Assuming a body weight of 80 kg, our model estimates V1 = 10.3 l before CPB and 11.9 l during and after CPB; V2 = 8.5 l before CPB and 9.8 l during and after CPB; Cl1 = 0.15 l/s before CPB, 0.11 l/s during CPB, and 0.17 l/s after CPB; and Cl2 = 0.18 l/s before CPB and 0.21 l/s during and after CPB. Based on simulation of previous studies of TA efficacy, we estimate that a 30-min loading dose of 12.5 mg/kg with a maintenance infusion of 6.5 mg x kg(-1) x hr(-1) and 1 mg/kg added to the pump prime will maintain TA concentration greater than 334 microm, and a higher dose based on 30 mg/kg loading dose plus 16 mg x kg(-1) x h(-1) continuous infusion and 2 mg/kg added to the pump prime would maintain TA concentrations greater than 800 microm. Tranexamic acid pharmacokinetics are influenced by CPB. Our TA pharmacokinetic model does not provide support for the wide range of TA dosing techniques that have been reported. Variation in TA efficacy from study to study and confusion about the optimal duration of TA treatment may be the result of dosing techniques that do not maintain stable, therapeutic TA concentrations.
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                Author and article information

                Contributors
                trhsbcq@163.com
                gao_xurong@163.com
                mayiyan91@163.com
                lvhuanran0413@sina.com
                huwenjun305@163.com
                zhshjwan@sina.com
                ji_hongwen@sina.com
                guyanwang2008@163.com
                shjfuwai@sina.com
                Journal
                BMC Anesthesiol
                BMC Anesthesiol
                BMC Anesthesiology
                BioMed Central (London )
                1471-2253
                15 July 2019
                15 July 2019
                2019
                : 19
                : 129
                Affiliations
                [1 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, Department of Anesthesiology, Fuwai Hospital, National Center for Cardiovascular Diseases, , Chinese Academy of Medical Sciences, and Peking Union Medical College, ; No.167 Beilishi Road, Xicheng district, Beijing, China
                [2 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, Department of Blood Transfusion, Fuwai Hospital, National Center for Cardiovascular Diseases, , Chinese Academy of Medical Sciences, and Peking Union Medical College, ; No.167 Beilishi Road, Xicheng district, Beijing, China
                [3 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, Operating room, Fuwai Hospital, National Center for Cardiovascular Diseases, , Chinese Academy of Medical Sciences, and Peking Union Medical College, ; No.167 Beilishi Road, Xicheng district, Beijing, China
                [4 ]ISNI 0000 0001 2267 2324, GRID grid.488137.1, Department of Anesthesiology, , The 305th Hospital of the Chinese People’s Liberation Army, ; No.13 Wenjin Road, Xicheng district, Beijing, China
                [5 ]Department of Anesthesiology, Wu’an First People’s Hospital, Kuangjian Road, Handan, Hebei Province China
                Author information
                http://orcid.org/0000-0002-7406-3560
                Article
                772
                10.1186/s12871-019-0772-0
                6631782
                31307381
                c09d8055-05ec-469f-834e-3314def314f4
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 September 2018
                : 28 May 2019
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Anesthesiology & Pain management
                tranexamic acid,cardiac surgery,seizure,dose regimen
                Anesthesiology & Pain management
                tranexamic acid, cardiac surgery, seizure, dose regimen

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