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Topical and Intravenous Tranexamic Acid in Acyanotic Children Undergoing Congenital Heart Surgery: A Randomized Clinical Trial
Bigdelian H, Montazeri M, Sedighi M, Mansouri M, Amanollahi A
The Journal of surgical research. 2023;288:64-70
Abstract
INTRODUCTION Postoperative bleeding is a common complication in congenital heart surgery. We aimed to evaluate effects of topical and intravenous tranexamic acid (TXA) administration on postoperative hemoglobin and bleeding in children with acyanotic congenital heart disease (CHD). METHODS In this randomized clinical trial, 50 acyanotic CHD children were allocated into two groups of topical (n = 25) and infusion (n = 25). Children in the infusion group were given intravenous TXA 50 mg/kg(-1) after sternotomy. Children in topical group were given 50 mg/kg(-1) TXA added to 20 mL of saline intrapericardially before sternal closure. Primary endpoint of study was comparison of postoperative hemoglobin and bleeding between topical and infusion groups. A linear mixed model (LMM) was used to estimate longitudinal changes in postoperative endpoints. RESULTS We did not observe significant differences in children's characteristics between two groups. Also, intraoperative and postoperative outcomes did not differ between two groups but children with intravenous TXA experienced significantly longer intubation time than topical children (P = 0.047). LMM analysis revealed that postoperative bleeding in topical group was lower compared to infusion group (P = 0.036). Also, age of children had a significant effect on mean changes of hemoglobin during postoperative care (β = -0.27, P = 0.030). No children died and none had serious postoperative complications such as seizures and reoperation. CONCLUSIONS We found that topical TXA is not superior to intravenous administration in management of blood loss. Also, no additional effect was found about topical TXA in further reducing transfusion rates and postoperative complications in acyanotic CHD children undergoing cardiac surgery.
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Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery
Marcucci, M., Painter, T. W., Conen, D., Leslie, K., Lomivorotov, V. V., Sessler, D., Chan, M. T. V., Borges, F. K., Martínez Zapata, M. J., Wang, C. Y., et al
Trials. 2022;23(1):101
Abstract
BACKGROUND For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. METHODS The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. DISCUSSION Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. TRIAL REGISTRATION ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.
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Effect of High- vs Low-Dose Tranexamic Acid Infusion on Need for Red Blood Cell Transfusion and Adverse Events in Patients Undergoing Cardiac Surgery: The OPTIMAL Randomized Clinical Trial
Shi, J., Zhou, C., Pan, W., Sun, H., Liu, S., Feng, W., Wang, W., Cheng, Z., Wang, Y., Zheng, Z.
Jama. 2022;328(4):336-347
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Abstract
IMPORTANCE Tranexamic acid is recommended for reducing blood loss and transfusion in cardiac surgery. However, it remains unknown whether a high dose of tranexamic acid provides better blood-sparing effect than a low dose without increasing the risk of thrombotic complications or seizures in cardiac surgery. OBJECTIVE To compare the efficacy and adverse events of high-dose vs low-dose tranexamic acid in patients undergoing cardiac surgery with cardiopulmonary bypass. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized clinical trial among adult patients undergoing cardiac surgery with cardiopulmonary bypass. The study enrolled 3079 patients at 4 hospitals in China from December 26, 2018, to April 21, 2021; final follow-up was on May 21, 2021. INTERVENTIONS Participants received either a high-dose tranexamic acid regimen comprising a 30-mg/kg bolus, a 16-mg/kg/h maintenance dose, and a 2-mg/kg prime (n = 1525) or a low-dose regimen comprising a 10-mg/kg bolus, a 2-mg/kg/h maintenance dose, and a 1-mg/kg prime (n = 1506). MAIN OUTCOMES AND MEASURES The primary efficacy end point was the rate of allogeneic red blood cell transfusion after start of operation (superiority hypothesis), and the primary safety end point was a composite of the 30-day postoperative rate of mortality, seizure, kidney dysfunction (stage 2 or 3 Kidney Disease: Improving Global Outcomes [KDIGO] criteria), and thrombotic events (myocardial infarction, ischemic stroke, deep vein thrombosis, and pulmonary embolism) (noninferiority hypothesis with a margin of 5%). There were 15 secondary end points, including the individual components of the primary safety end point. RESULTS Among 3079 patients who were randomized to treatment groups (mean age, 52.8 years; 38.1% women), 3031 (98.4%) completed the trial. Allogeneic red blood cell transfusion occurred in 333 of 1525 patients (21.8%) in the high-dose group and 391 of 1506 patients (26.0%) in the low-dose group (risk difference [RD], -4.1% [1-sided 97.55% CI, -∞ to -1.1%]; relative risk, 0.84 [1-sided 97.55% CI, -∞ to 0.96; P = .004]). The composite of postoperative seizure, thrombotic events, kidney dysfunction, and death occurred in 265 patients in the high-dose group (17.6%) and 249 patients in the low-dose group (16.8%) (RD, 0.8%; 1-sided 97.55% CI, -∞ to 3.9%; P = .003 for noninferiority). Fourteen of the 15 prespecified secondary end points were not significantly different between groups, including seizure, which occurred in 15 patients (1.0%) in the high-dose group and 6 patients (0.4%) in the low-dose group (RD, 0.6%; 95% CI, -0.0% to 1.2%; P = .05). CONCLUSIONS AND RELEVANCE Among patients who underwent cardiac surgery with cardiopulmonary bypass, high-dose compared with low-dose tranexamic acid infusion resulted in a modest statistically significant reduction in the proportion of patients who received allogeneic red blood cell transfusion and met criteria for noninferiority with respect to a composite primary safety end point consisting of 30-day mortality, seizure, kidney dysfunction, and thrombotic events. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03782350.
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Comparison of the in-vivo effect of two tranexamic acid doses on fibrinolysis parameters in adults undergoing valvular cardiac surgery with cardiopulmonary bypass - a pilot investigation
Zhou ZF, Zhai W, Yu LN, Sun K, Sun LH, Xing XF, Yan M
BMC anesthesiology. 2021;21(1):33
Abstract
BACKGROUND The blood saving efficacy of TXA in cardiac surgery has been proved in several studies, but TXA dosing regimens were varied in those studies. Therefore, we performed this study to investigate if there is a dose dependent in-vivo effect of TXA on fibrinolysis parameters by measurement of fibrinolysis markers in adults undergoing cardiac surgery with CPB. METHODS A double-blind, randomized, controlled prospective trial was conducted from February 11, 2017 to May 05, 2017. Thirty patients undergoing cardiac valve surgery were identified and randomly divided into a placebo group, low-dose group and high-dose group by 1: 1: 1. Fibrinolysis parameters were measured by plasma levels of D-Dimers, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-antiplasmin complex (PAP), tissue plasminogen activator (tPA) and thrombomodulin (TM). Those proteins were measured at five different sample times: preoperatively before the TXA injection (T(1)), 5 min after the TXA bolus (T(2)), 5 min after the initiation of CPB (T(3)), 5 min before the end of CPB (T(4)) and 5 min after the protamine administration (T(5)). A Thrombelastography (TEG) and standard coagulation test were also performed. RESULTS Compared with the control group, the level of the D-Dimers decreased in the low-dose and high-dose groups when the patients arrived at the ICU and on the first postoperative morning. Over time, the concentrations of PAI-1, TAFI, and TM, but not PAP and tPA, showed significant differences between the three groups (P < 0.05). Compared with the placebo group, the plasma concentrations of PAI-1 and TAFI decreased significantly at the T3 and T4 (P < 0.05); TAFI concentrations also decreased at the T5 in low-dose group (P < 0.05). Compared with the low-dose group, the concentration of TM increased significantly at the T4 in high-dose group. CONCLUSIONS The in-vivo effect of low dose TXA is equivalent to high dose TXA on fibrinolysis parameters in adults with a low bleeding risk undergoing valvular cardiac surgery with cardiopulmonary bypass, and a low dose TXA regimen might be equivalent to high dose TXA for those patients. TRIAL REGISTRATION ChiCTR-IPR-17010303 , Principal investigator: Zhen-feng ZHOU, Date of registration: January 1, 2017.
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Analysis of serum tranexamic acid in patients undergoing open heart surgery
Ivica, J., Gauthier, J., Power, P., Lamy, A., Potter, M.
Clinical Biochemistry. 2021;87:74-78
Abstract
BACKGROUND Tranexamic acid is a drug used during open cardiac surgery to prevent blood loss. The blood levels of 10-100 µg/mL are reported to be in the therapeutic range and higher levels are linked to increased incidence of adverse effects. The aim of this study was to optimize and validate an LC-MS/MS method for serum tranexamic acid and measure its levels in patients from the DEPOSITION Pilot trial in order to prove the concept that topical administration will yield lower serum concentration. METHODS The method development was carried out in several steps including sample preparation, and optimization of chromatography and tandem mass spectrometry parameters. Method validation including day-to-day precision with 4 QC levels, limit of detection, sample stability, carryover, and concentration-signal linearity was carried out. Ninety patient samples were analyzed using the validated method. RESULTS Fast and efficient LC-MS/MS method for analysis of tranexamic acid in serum was developed. The run time was 7 min with the total time of one hour including the sample preparation. The method precision was acceptable (%CV = 10.5-12.6%) with no sample carryover observed. The matrix effect on the analytical sensitivity was negligible and the lower limit of detection was 0.5 µg/mL. The difference in the mean adjusted concentrations between topical (45 patients) and intravenous (45 patients) groups was statistically significant (0.1154 µg/mL/kg vs. 0.2542 µg/mL/kg, p < 0.0001) CONCLUSIONS Rapid and simple LC-MS/MS method for analysis of tranexamic acid was optimized and validated. The laboratory has played a crucial role in proving the concept that topical administration yields significantly lower systemic levels of tranexamic acid, and thus decreases the risk of adverse outcomes in patients undergoing open cardiac surgery.
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The synergistic effect of tranexamic acid and ethamsylate combination on blood loss in pediatric cardiac surgery
El Baser IIA, ElBendary HM, ElDerie A
Annals of cardiac anaesthesia. 2021;24(1):17-23
Abstract
BACKGROUND Pediatric patients are at risk for bleeding after cardiac surgery. Administration of antifibrinolytic agents reduces postoperative blood loss. OBJECTIVE Evaluation of the efficacy of combined administration of tranexamic acid (TXA) and ethamsylate in the reduction of postoperative blood loss in pediatric cardiac surgery. METHODS This prospective randomized study included 126 children submitted for cardiac surgery, and they were allocated into three groups: control group (n = 42); TXA group (n = 42):- received only TXA; and combined ethamsylate TXA group (n = 42):- received a combination of TXA and ethamsylate. The main collected data included sternal closure time, the needs for intraoperative transfusion of blood and its products, the total amount of blood loss, and the amount of the whole blood and its products transfused to the patients in the first 24 postoperative hours. RESULTS Blood loss volume in the first 24 postoperative hours was significantly smaller in combined group than the TXA and control groups and was significantly smaller in the TXA group than the control group. The sternal closure time was significantly shorter in the combined group than the other 2 groups and significantly shorter in TXA than the control group. The amount of whole blood transfused to patients in the combined group during surgery and in the first postoperative 24 h was significantly smaller than the other 2 groups and smaller in TXA group than the control group during surgery. CONCLUSION Combined administration of ethamsylate and TXA in pediatric cardiac surgery was more effective in reducing postoperative blood loss and whole blood transfusion requirements than the administration of TXA alone.
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Antifibrinolytic Drugs for the Prevention of Bleeding in Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Systematic Review and Meta-analysis
Siemens K, Sangaran DP, Hunt BJ, Murdoch IA, Tibby SM
Anesthesia and analgesia. 2021
Abstract
BACKGROUND Bleeding is one of the commonest complications affecting children undergoing cardiac surgery on cardiopulmonary bypass. Antifibrinolytic drugs are part of a multifaceted approach aimed at reducing bleeding, though sufficiently sized pediatric studies are sparse, and dosing algorithms are heterogeneous. Our objective was to evaluate the efficacy and safety of antifibrinolytic agents as well as the effectiveness of different dosing regimens in pediatric cardiac surgery using cardiopulmonary bypass. METHODS We performed a systematic review and meta-analysis evaluating randomized controlled trials published between 1980 and 2019, identified by searching the databases MEDLINE, EMBASE, PubMed, and CENTRAL. All studies investigating patients <18 years of age without underlying hematological disorders were included. The primary outcome was postoperative bleeding; secondary end points included blood product transfusion, mortality, and safety (thromboses, anaphylaxis, renal or neurological dysfunction, and seizures). Different dosing regimens were compared. Studies were dual appraised, outcomes were reported descriptively and, if appropriate, quantitatively using the Review Manager 5 (REVMAN 5) software (The Cochrane Collaboration). RESULTS Thirty of 209 articles were included, evaluating the following drugs versus control: aprotinin n = 14, tranexamic acid (TXA) n = 12, and epsilon-aminocaproic acid (EACA) n = 4. The number of participants per intervention group ranged from 11 to 100 (median, 25; interquartile range [IQR], 20.5) with a wide age span (mean, 13 days to 5.8 years) and weight range (mean, 3.1-26.3 kg). Methodological quality was low to moderate.All agents reduced mean 24-hour blood loss compared to control: aprotinin by 6.0 mL/kg (95% confidence interval [CI], -9.1 to -3.0; P = .0001), TXA by 9.0 mL/kg (95% CI, -11.3 to -6.8; P < .00001), and EACA by 10.5 mL/kg (95% CI, -21.1 to 0.0; P = .05). Heterogeneity was low for TXA (I2 = 29%; P = .19), moderate for aprotinin (I2 = 41%; P = .11), and high for EACA (I2 = 95%; P = <.00001). All agents also reduced 24-hour blood product transfusion. There was no clear dose-response effect for TXA nor aprotinin. Studies were underpowered to detect significant differences in mortality, thromboses, anaphylaxis, and renal or neurological dysfunction. CONCLUSIONS The available data demonstrate efficacy for all 3 antifibrinolytic drugs. Therefore, the agent with the most favorable safety profile should be used. As sufficient data are lacking, large comparative trials are warranted to assess the relative safety and appropriate dosing regimens in pediatrics.
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The effect of tranexamic acid in reducing postoperative hemorrhage in patients undergoing coronary artery bypass graft
Rostami A, Hoseini AH, Kamali A
Saudi journal of anaesthesia. 2020;14(4):431-435
Abstract
INTRODUCTION Nowadays, cardiovascular diseases such as coronary heart disease are one of the most important causes of human mortality worldwide. Coronary artery bypass graft (CABG) surgery is a standard therapy approach for those suffering from coronary artery disease. Tranexamic acid (TXA), an antifibrinolytic drug, which, in turn, inhibits fibrinolysis, leading to the prevention of bleeding, thus, the present study aimed to evaluate the effect of topical TXA on bleeding reduction after coronary artery CABG. MATERIALS AND METHODS In this study 62 patients were randomly divided into two groups of TXA and control. After surgery and removal from the cardiopulmonary pump, TXA (2 g) was injected locally into the mediastinum by the surgeon. In the second group (control) the same amount of normal saline (100 cc) was given. Data were analyzed by SPSS 19 software via the t-test and Fisher's test. RESULTS A significant difference was found between the 2 groups in terms of postoperative hemorrhage, packed cell volume, platelet transfusion, duration of surgery, and received FFP (P = 0.0001; P = 0.01; P = 0.0001; P = 0.0001; P = 0.0001), where were found to be lower in the TXA group than in the placebo group. There was no significant difference in age, sex, return to the operating room, and discharge. CONCLUSION The use of topical TXA in GABC significantly reduced postoperative hemorrhage, packed cell volume, platelet transfusion, and FFP after surgery. Besides, it had no significant effect on the return to the operating room and mortality.
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Topical versus low-dose systemic tranexamic acid in pediatric cardiac surgery: A randomized clinical study
Hatami F, Valizadeh N, Salehi F, Hosseinzadeh Maleki M
Journal of cardiac surgery. 2020
Abstract
OBJECTIVES The current study aimed to compare the benefits of topical and low-dose systemic tranexamic acid administration in pediatric cardiac surgery. METHODS A total of 117 children undergoing cardiac surgery for congenital heart disease were assigned into three groups. Patients in the systemic group received 20 mg/kg(-1) tranexamic acid through the cardiopulmonary bypass followed by another dose of 20 mg/kg(-1) after cardiopulmonary bypass separation. Patients in the topical group were administered with 50 mg/kg(-1) tranexamic acid poured into the pericardium, while the control group received no antifibrinolytics. The outcome measures of bleeding and blood products transfusion were recorded over the first 48 h postoperatively. RESULTS Chest tube drainage was significantly lower in both topical and systemic groups than the control group, but it did not differ between the case groups. Blood products requirement did not show a difference between groups. Neurological or thromboembolic events did not variate among the groups, and no deaths occurred in this study. CONCLUSION Topical or systemic tranexamic acid administration reduced postoperative blood loss effectively without adding an extra risk.
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Comparison of effectiveness of tranexamic acid and epsilon-amino-caproic-acid in decreasing postoperative bleeding in off-pump CABG surgeries: A prospective, randomized, double-blind study
Verma S, Srinivas U, Sathpathy AK, Mittal P
Annals of cardiac anaesthesia. 2020;23(1):65-69
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Abstract
Context: Off-pump coronary artery bypass graft (CABG) surgeries have been shown to have increased fibrinolysis due to tissue plasminogen activator release. There are no trials comparing the two available antifibrinolytics (tranexemic acid and epsilon-amino-caproic acid) in off-pump CABG surgeries. Aims: The aim of the present study was to compare the effectiveness of tranexamic acid and epsilon-amino-caproic acid with respect to postoperative bleeding at 4 and 24 hours as the primary outcome, and rate of postoperative transfusion, re-operations, complication rate, serum fibrinogen, and D-dimer levels as secondary outcomes. Settings and Design: The study was carried out at a tertiary-level hospital between June 2017 and June 2018. It was a prospective, randomized, double-blind study. Materials and Methods: Eighty patients undergoing off-pump CABG, were randomly allocated to receive tranexamic acid or epsilon-amino-caproic acid. The patients were followed up in the postoperative period and were assessed for primary and secondary outcomes. Statistical Analysis Used: Statistical analysis was performed using SPSS software, version 19.0 (SPSS Inc., Chicago, IL). Nonparametric data were expressed as median with interquartile range and compared using Mann-Whitney U-test, parametric data was represented as mean with standard deviation and analyzed using Student's t-test. Nominal data were analyzed using Chi-square test. Results: Bleeding at 4 hours did not show significant difference between groups, 180 ml (80-250) vs 200 ml (100-310). Bleeding at 24 hours was significantly lesser in tranexamic acid group as compared to epsilon-amino-caproic acid group, 350 ml (130-520) vs 430 ml (160-730) (P = 0.0022) The rate of transfusion, re-operations, seizures, renal dysfunction, fibrinogen levels, and D-dimer levels did not show significant difference between the groups. Conclusions: Tranexamic acid significantly reduced postoperative bleeding in off-pump CABG at 24 hours as compared to epsilon-amino-caproic-acid.
PICO Summary
Population
Patients undergoing off-pump CABG, (n=76).
Intervention
Tranexamic acid, (n=38).
Comparison
Epsilon-amino-caproic acid, (n=38).
Outcome
Bleeding at 4 hours did not show significant difference between groups, 180 ml (80-250) vs 200 ml (100-310). Bleeding at 24 hours was significantly lesser in tranexamic acid group as compared to epsilon-amino-caproic acid group, 350 ml (130-520) vs 430 ml (160-730). The rate of transfusion, re-operations, seizures, renal dysfunction, fibrinogen levels, and D-dimer levels did not show significant difference between the groups.