Antifibrinolytic Drugs for the Prevention of Bleeding in Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Systematic Review and Meta-analysis
Anesthesia and analgesia. 2021
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.
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
BMC anesthesiology. 2021;21(1):33
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.
The synergistic effect of tranexamic acid and ethamsylate combination on blood loss in pediatric cardiac surgery
Annals of cardiac anaesthesia. 2021;24(1):17-23
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.
Intravenous Tranexamic Acid Decreases Blood Transfusion in Off-Pump Coronary Artery Bypass Surgery: A Meta-analysis
The heart surgery forum. 2020;23(1):E039-e049
BACKGROUND Tranexamic acid (TXA) has been widely used during on-pump coronary artery bypass graft (CABG) surgery owing to its antifibrinolytic effect. However, the efficacy and safety of TXA in off-pump CABG surgery remains unconfirmed, especially intravenous (IV) administration. OBJECTIVE The aim of this study was to evaluate the effectiveness and safety of IV administration of TXA in off-pump CABG settings. METHODS AND RESULTS A comprehensive literature search was performed to identify randomized controlled trials (RCTs) that compared IV use of TXA with placebo in the reduction of postoperative 24-hour blood transfusion, as well as postoperative death and thrombotic events. The combined estimations were compiled with a fixed-effects model or, if heterogeneity existed, a random-effects model. Funnel plots and Egger's test were used to assess potential publication bias. Subgroup analyses were used to explore possible sources of heterogeneity. In total, 12 RCTs met the inclusion criteria. IV administration of TXA significantly reduced the risk of packed red blood cell (PRBC) transfusion [risk ratio (RR) = 0.61, 95% confidence interval (CI) 0.503 to 0.756, P < .001, I2 = 0.0%) during the 24 hours after surgery. However, there was no statistical significance in platelet (RR = 0.613, 95% CI 0.112 to 3.348, P = .572, I2 = 0.0%) or total fresh frozen plasma (FFP) (RR = 0.511, 95% CI 0.246 to 1.063, P = .073, I2 = 0.0%) transfusion. Also, no significant difference was found in major adverse events (death or thrombotic complications) (RR = 0.917, 95% CI 0.532 to 1.581, P = .756, I2 = 0.0%) between the 2 groups. Interestingly, further subgroup analysis demonstrated that IV TXA decreased the risk of prothrombin time (PT)- and international normalized ratio (INR)-guided FFP transfusion (RR = 0.462, 95% CI 0.296 to 0.721, P = .001, I2 = 0.0%). CONCLUSION IV TXA was effective in reducing allogeneic blood component transfusion (PRBCs and PT- or INR-guided FFP transfusion), without increasing the incidence of postoperative death or thrombotic complications in off-pump CAB surgery.
The effect of tranexamic acid in reducing postoperative hemorrhage in patients undergoing coronary artery bypass graft
Saudi journal of anaesthesia. 2020;14(4):431-435
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.
Topical versus low-dose systemic tranexamic acid in pediatric cardiac surgery: A randomized clinical study
Journal of cardiac surgery. 2020
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.
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
Annals of cardiac anaesthesia. 2020;23(1):65-69
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.
Patients undergoing off-pump CABG, (n=76).
Tranexamic acid, (n=38).
Epsilon-amino-caproic acid, (n=38).
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.
Comparison Effect of Tranexamic Acid (TA) and Tranexamic Acid Combined with Vitamin C (TXC) on Drainage Volume and Atrial Fibrillation Arrhythmia in Patients Undergoing Cardiac Bypass Surgery: Randomized Clinical Trial
Anesthesiology and pain medicine. 2019;9(5):e96096
Background: Tranexamic acid and vitamin C are potent antifibrinolytic and oxidative stress agents that reduce blood loss and transfusion blood in cardiopulmonary bypass (CPB). Objectives: The aim of this study was to evaluate the efficacy of tranexamic acid (TA) and tranexamic acid combined with vitamin C (TXC) on drainage volume (blood loss) and atrial fibrillation (AF) in patients undergoing cardiac bypass surgery in Gorgan, Shafa hospital, Iran. Methods: This study is a double-blind randomized clinical trial. A sample size of 120 candidates of cardiac bypass surgery were included in this prospective study. Patients were randomly assigned to treatments in two groups. In both groups, 50 mg/kg tranexamic acid was administered intravenously directly before sternotomy: group A (N = 58) patients received tranexamic acid (TA) only and group B (N = 62) tranexamic acid with vitamin C (TXC) half an hour before surgery and 2 g vitamin C with 100 mL 0.9% saline were injected. Subsequently, during 4 days after surgery, 1000 mg of vitamin C and 100 cc 0.9% saline was infused every day. Intraoperative and postoperative blood loss (volume of blood in the drain) and atrial fibrillation complications were recorded for 24 hours after the operation. Results: The patients who received vitamin C had less bleeding during operation and in the early hours post-operation. Patients in (TA) group had mean drainage of 34.41 milliliter more than patients in (TXC) group (P < 0.001). Chi-square test showed that arrhythmia (AF) condition was the same in the two groups during 14 times of study (four times during operation and ten times up to 24 hours after the operation), and AF arrhythmia in the two groups was less than 5%. Conclusions: In this study tranexamic acid with vitamin C have a positive effect on the amount of drainage (blood loss) and there was no significant difference in the incidence of AF between two groups.
Tranexamic acid in open aortic aneurysm surgery: a randomised clinical trial
British journal of anaesthesia. 2019
BACKGROUND Bleeding and transfusions affect mortality in aortic surgery. Although tranexamic acid significantly reduced bleeding in multiple settings, its role in major vascular surgery was never studied. The aim of this study was to determine if tranexamic acid reduces blood loss in open abdominal aortic aneurysm (AAA) surgery. METHODS A total of 100 patients undergoing elective open AAA repair were randomised to receive tranexamic acid (a loading dose of 500 mg and a continuous infusion of 250 mg h(-1)) or placebo. The primary outcome was intraoperative blood loss, and the secondary outcomes were the number of patients receiving red blood cells, occurrence of thromboembolic events, and mortality. Data were analysed using the intention-to-treat principle. RESULTS Fifty patients were randomised into each group. Median (inter-quartile range) intraoperative blood loss was 400 (300-1050) ml in the tranexamic acid group vs 500 (360-1000) ml in the placebo group (P=0.44). Transfusion rate was seven/50 (14%) in the tranexamic group vs 12/50 (24%) in the placebo group (P=0.20). No thrombosis was recorded. In a post hoc analysis, postoperative blood loss was reduced in the tranexamic group both at 4 h (60 [40-80] ml vs 100 [60-140] ml, P<0.001) and 24 h (180 [120-275] vs 275 [190-395] ml, P=0.003) after surgery. At 1 yr, three patients were dead, all in the placebo group (P=0.24) and all after 28 days. CONCLUSIONS Tranexamic acid did not reduce intraoperative blood loss or blood transfusions in open AAA repair, although it may reduce postoperative blood loss without increasing adverse effects. CLINICAL TRIAL REGISTRATION NCT02335359.
Exclusion criteria and adverse events in perioperative trials of tranexamic acid in cardiac surgery: a systematic review and meta-analysis
Canadian journal of anaesthesia = Journal canadien d'anesthesie. 2019
PURPOSE Tranexamic acid (TXA) reduces perioperative blood loss and transfusion requirement following cardiac surgery. Nevertheless, TXA remains underutilized because of concerns regarding development of adverse events. We conducted a systematic review to determine which patients are commonly excluded from TXA cardiac surgery clinical trials to determine if there are patient groups lacking safety data on TXA. METHODS The databases Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched until September 2017. Eligible studies were randomized-controlled trials (RCTs) administering systemic TXA perioperatively to patients undergoing any cardiac surgery. Our primary outcome was the exclusion criteria for each RCT, and the secondary endpoint was TXA safety. A descriptive synthesis was performed to analyze the exclusion criteria. TXA safety was assessed with meta-analysis. PRINCIPAL FINDINGS Seventy eligible RCTs were included. The most common reasons for excluding patients from TXA cardiac surgery trials were major hepatic, renal, or cardiac comorbidities (76% of studies). Meta-analysis showed that TXA did not increase the risk of adverse events compared with placebo or no intervention (risk ratio, 0.97; 95% confidence interval, 0.88 to 1.07), including thrombosis and seizure. CONCLUSION We found that systemic TXA is safe to use in cardiac surgery. Certain patient groups are frequently excluded from TXA cardiac surgery trials, and may consequently have limited efficacy and safety data on TXA. Further research in these patient groups may be needed; nevertheless, for many patient populations there are sufficient data to inform evidence-based guidelines for TXA use in cardiac surgery. TRIAL REGISTRATION PROSPERO (CRD42017060971); registered 4 April, 2017.