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Prophylactic Use of Antifibrinolytics During Pediatric Cardiac Surgery With Cardiopulmonary Bypass on Postoperative Bleeding and Transfusion: A Systematic Review and Meta-Analysis
Schertz K, Karam O, Demetres M, Faraoni S, Faraoni D, Nellis ME
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2022
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Editor's Choice
Abstract
OBJECTIVES To determine the effect of intraoperative antifibrinolytics, including tranexamic acid (TXA), aminocaproic acid (EACA), or aprotinin, on bleeding in children undergoing cardiac surgery with cardiopulmonary bypass (CPB). DATA SOURCES Relevant articles were systematically searched from Ovid MEDLINE, Ovid EMBASE, CINAHL, Cochrane Library, and Web of Science to November 15, 2021. STUDY SELECTION Abstracts were screened, and full texts were reviewed using predetermined inclusion and exclusion criteria using the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. DATA EXTRACTION A standardized data extraction tool was used. DATA SYNTHESIS Sixty-eight studies including 28,735 patients were analyzed. TXA compared with placebo resulted in a mean decrease in chest tube output of 9.1 mL/kg (95% CI, 6.0-12.3 mL/kg), I2 equals to 65.2%, p value of less than 0.001, platelet requirement of 2.9 mL/kg (95% CI, 0.1-5.8 mL/kg), I2=72.5%, p value less than 0.001 and plasma requirement of 4.0 mL/kg (95% CI, 0.6-7.2 mL/kg), I2 equals to 94.5%, p value less than0.001. Aprotinin compared with placebo resulted in a mean decrease in chest tube output of 4.3 mL/kg (2.4-6.2 mL/kg), I2 equals to 66.3%, p value of less than 0.001, platelet transfusion of 4.6 mL/kg (95% CI, 0.6-8.6 mL/kg), I2 equals to 93.6%, p value of less than 0.001, and plasma transfusion of 7.7 mL/kg (95% CI, 2.1-13.2 mL/kg), I2 equals to 95.3%, p value of less than 0.001. EACA compared with placebo resulted in a mean decrease in chest tube output of 9.2 mL/kg (2.3-21.0 mL/kg), I2 equals to 96.4%, p value of less than 0.001, RBC transfusion of 7.2 mL/kg (95% CI, 2.4-12.1 mL/kg), I2 equals to 94.5%, p value equals to 0.002, and platelet transfusion of 10.7 mL/kg (95% CI, 2.9-18.5 mL/kg), I2 equals to 0%, p value of less than 0.001. No statistical difference was observed in chest tube output when TXA was compared with aprotinin. Subgroup analysis of cyanotic patients showed a significant decrease in chest tube output, platelet requirement, and plasma requirement for patients receiving aprotinin. Overall, the quality of evidence was moderate. CONCLUSIONS Antifibrinolytics are effective at decreasing blood loss and blood product requirement in children undergoing cardiac surgery with CPB although the quality of evidence is only moderate.
PICO Summary
Population
Children undergoing cardiac surgery with cardiopulmonary bypass, (68 studies, n= 28,735).
Intervention
Intraoperative antifibrinolytics, including tranexamic acid (TXA), aminocaproic acid (EACA), or aprotinin.
Comparison
Placebo.
Outcome
TXA compared with placebo resulted in a mean decrease in chest tube output of 9.1 mL/kg (95% Confidence Interval (CI): 6.0-12.3 mL/kg), platelet requirement of 2.9 mL/kg (95% CI: 0.1-5.8 mL/kg), and plasma requirement of 4.0 mL/kg (95% CI: 0.6-7.2 mL/kg). Aprotinin compared with placebo resulted in a mean decrease in chest tube output of 4.3 mL/kg (2.4-6.2 mL/kg), platelet transfusion of 4.6 mL/kg (95% CI: 0.6-8.6 mL/kg), and plasma transfusion of 7.7 mL/kg (95% CI: 2.1-13.2 mL/kg). EACA compared with placebo resulted in a mean decrease in chest tube output of 9.2 mL/kg (2.3-21.0 mL/kg), red blood cell transfusion of 7.2 mL/kg (95% CI: 2.4-12.1 mL/kg), and platelet transfusion of 10.7 mL/kg (95% CI: 2.9-18.5 mL/kg). Overall, the quality of evidence was moderate.
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Tranexamic acid reduces postoperative blood loss in Chinese pediatric patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis
Zou ZY, He LX, Yao YT
Medicine. 2022;101(9):e28966
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Abstract
BACKGROUND Tranexamic acid has been increasingly used for blood conservation in cardiac surgery. However, the evidence supporting the routine use of tranexamic acid in Chinese pediatric patients undergoing cardiac surgery remains weak. This meta-analysis aimed to systematically review the efficacy of tranexamic acid when applying to Chinese pediatric patients undergoing cardiac surgery. PARTICIPANTS Chinese pediatric patients undergoing cardiac surgery. INTERVENTIONS Tranexamic acid or control drugs (saline/blank). METHODS PUBMED, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Data till May 4, 2021, database search was updated on August 1. Primary outcomes of interest included postoperative bleeding, allogeneic transfusion, and reoperation for bleeding. Secondary outcomes of interest included postoperative recovery. For continuous/dichotomous variables, treatment effects were calculated as weighted mean difference (WMD)/odds ratio and 95% confidence interval. RESULTS A database search yielded 15 randomized controlled trials including 1641 patients, where 8 studies were allocated into non-cyanotic congenital group, 5 were allocated into cyanotic congenital group, and the other 2 were allocated into combined cyanotic/non-cyanotic group. This meta-analysis demonstrate that tranexamic acid administration can reduce the postoperative 24 hours blood loss in non-cyanotic, cyanotic, and combined cyanotic/non-cyanotic patients, the red blood cell transfusion in non-cyanotic and cyanotic patients, and the fresh frozen plasma transfusion in non-cyanotic and combined cyanotic/non-cyanotic patients. CONCLUSION This meta-analysis demonstrates that tranexamic acid is highly effective in reducing the blood loss in Chinese pediatric cardiac surgery, but it behaves poorly when it comes to the transfusion requirement. To further confirm this, more well-designed and adequately-powered randomized trials are needed.
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Efficacy and safety of aprotinin in paediatric cardiac surgery: A systematic review and meta-analysis
Atasever AG, Eerens M, Van den Eynde R, Faraoni D, Rex S
European journal of anaesthesiology. 2021
Abstract
BACKGROUND The relicensing of aprotinin in Europe and Canada has stimulated discussions on its usefulness in paediatric cardiac surgery. OBJECTIVE To systematically evaluate the available evidence on the efficacy and safety of aprotinin in paediatric cardiac surgery. DESIGN Systematic review of all randomised and observational studies comparing aprotinin with tranexamic acid, epsilon aminocaproic acid, placebo or no drug in paediatric cardiac surgery. Meta-analyses were performed on efficacy and safety outcomes. DATA SOURCES PubMed, Cochrane Central Register of Controlled Trials, Web of Science and Embase were searched from January 2000 to March 2021. ELIGIBILITY CRITERIA Studies that enrolled children under 18 years undergoing cardiac surgery with cardiopulmonary bypass. RESULTS Thirty-two studies enrolling a total of 63 894 paediatric cardiac procedures were included. Aprotinin significantly reduced total blood loss [mean difference -4.70 ml kg-1, 95% confidence interval (CI), -7.88 to -1.53; P = 0.004], postoperative transfusion requirements and the incidence of surgical re-exploration for bleeding [odds ratio (OR) 0.74, 95% CI, 0.56 to 0.97; P = 0.03]. Aprotinin had no effects on 30-day mortality (OR 1.02, 95% CI, 0.93 to 1.11; P = 0.73) and on other safety outcomes, except for the incidence of renal replacement therapy (RRT), which was significantly increased in patients given aprotinin (OR 1.29, 95% CI, 1.08 to 1.54; P = 0.006). Findings from observational and randomised controlled trials did not largely differ. A sub-group analysis in neonates showed that aprotinin significantly reduced packed red blood cell transfusions and the incidence of postoperative surgical re-exploration for bleeding and/or tamponade. When compared with lysine analogues, aprotinin was more effective at reducing bleeding and transfusion without increasing the risk of side effects. CONCLUSION This meta-analysis suggests that aprotinin is effective and well tolerated in paediatric cardiac surgery. Given the large heterogeneity of the results and the risk of selection bias in observational studies, large randomised controlled trials are warranted.
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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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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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Epsilon aminocaproic acid reduces blood transfusion and improves the coagulation test after pediatric open-heart surgery: a meta-analysis of 5 clinical trials
Lu J, Meng H, Meng Z, Sun Y, Pribis JP, Zhu C, Li Q
International Journal of Clinical & Experimental Pathology. 2015;8((7)):7978-87.
Abstract
BACKGROUND Excessive postoperative blood loss after cardiopulmonary bypass is a common problem, especially in patients suffering from congenital heart diseases. The efficacy of epsilon aminocaproic acid (EACA) as a prophylactic treatment for postoperative bleeding after pediatric open-heart surgery has not been determined. This meta-analysis investigates the efficacy of EACA in the minimization of bleeding and blood transfusion and the maintenance of coagulation tests after pediatric open-heart surgery. METHODS A comprehensive literature search was performed to identify all randomized clinical trials on the subject. PubMed, Embase, the Cochrane Library, and the Chinese Medical Journal Network were screened. The primary outcome used for the analysis was postoperative blood loss. Secondary outcomes included postoperative blood transfusion, re-exploration rate and postoperative coagulation tests. The mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) were used as summary statistics. RESULTS Five trials were included in this meta-analysis of 515 patients. Prophylactic EACA was associated with a reduction in postoperative blood loss, but this difference did not reach statistical significance (MD: -7.08; 95% CI: -16.11 to 1.95; P = 0.12). Patients treated with EACA received fewer postoperative blood transfusions, including packed red blood cells (MD: -8.36; 95% CI: -12.63 to -4.09; P = 0.0001), fresh frozen plasma (MD: -3.85; 95% CI: -5.63 to -2.08; P < 0.0001), and platelet concentrate (MD: -10.66; 95% CI: -18.45 to -2.87; P = 0.007), and had a lower re-exploration rate (RR: 0.46; 95% CI: 0.23 to 0.92; P = 0.03). Prophylactic EACA also improved coagulation tests 6 hours after open-heart surgery. CONCLUSIONS Prophylactic EACA minimizes postoperative blood transfusion and helps maintain coagulation in pediatric patients undergoing open-heart surgery. Therefore, the results of this study indicate that adjunctive EACA is a good choice for the prevention of postoperative blood transfusion following pediatric cardiac surgery.
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Efficacy of tranexamic acid as compared to aprotinin in open heart surgery in children
Muthialu N, Balakrishnan S, Sundar R, Muralidharan S
Annals of Cardiac Anaesthesia. 2015;18((1):):23-6.
Abstract
BACKGROUND Coagulopathy is a major issue in children undergoing high-risk pediatric cardiac surgery. Use of anti-fibrinolytics is well documented in adults, but recently there are questions raised about safety and effectiveness of their use on routine use. Tranexamic acid is a potent anti-fibrinolytic, but its role is not fully understood in children. This study aims to study the benefits tranexamic acid in controlling postoperative bleeding in pediatric cardiac surgical patients. METHODS AND RESULTS Fifty consecutive children who underwent cardiac surgery were randomized prospectively to receive either aprotinin (Group A; n = 24) or tranexamic acid (Group B; n = 26) from September 2009 to February 2010 were studied. Primary end points were early mortality, postoperative drainage, reoperation for bleeding and complications. Mean age and body weight was smaller in Group A (Age: 48.55 vs. 64.73 months; weight 10.75 vs. 14.80 kg) respectively. Group A had more cyanotic heart disease than Group B (87.5% vs. 76.92%). Mean cardiopulmonary bypass time (144.33 vs. 84.34 min) and aortic cross-clamp time (78.5 vs. 41.46 min) were significantly higher in group A. While the blood and products usage was significantly higher in Group A, there was no difference in indexed postoperative drainage in first 4, 8 and 12 h and postoperative coagulation parameters. Mean C-reactive protein was less in Group A than B and renal dysfunction was seen more in Group A (25% vs. 7.6%). Mortality in Group A was 16.66% and 7.6% in Group B. CONCLUSION Anti-fibrinolytics have a definitive role in high-risk children who undergo open-heart surgery. Tranexamic acid is as equally effective as aprotinin with no additional increase in morbidity or mortality. Ultramini Abstract: Coagulopathy has been a major issue in pediatric cardiac surgery, and anti-fibrinolytics have been used fairly regularly in various settings. This study aims to evaluate the efficacy of tranexamic acid as compared against that of aprotinin in a randomized model. Tranexamic acid proves to be equally effective with less toxicity with no added mortality.
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Continuous or discontinuous tranexamic acid effectively inhibits fibrinolysis in children undergoing cardiac surgery with cardiopulmonary bypass
Couturier R, Rubatti M, Credico C, Louvain-Quintard V, Anerkian V, Doubine S, Vasse M, Grassin-Delyle S
Blood Coagulation & Fibrinolysis. 2014;25((3):):259-65.
Abstract
Tranexamic acid is given continuously or discontinuously as an anti-fibrinolytic therapy during cardiac surgery, but the effects on fibrinolysis parameters remain poorly investigated. We sought to assess the effects of continuous and discontinuous tranexamic acid on fibrinolysis parameters in children undergoing cardiac surgery with cardiopulmonary bypass (CPB). Children requiring cardiac surgery or repeat surgery by sternotomy with CPB for congenital heart disease were randomized to receive either continuous or discontinuous tranexamic acid. Blood tranexamic acid, D-dimers, tissue plasminogen activator (tPA), tPA-plasminogen activator inhibitor 1 (tPA-PAI1) complexes, fibrinogen and fibrin monomers were measured and compared to values obtained from children who did not receive tranexamic acid. Tranexamic acid inhibited the CPB-induced increase in D-dimers, with a similar potency between continuous and discontinuous regimens. Time courses for tPA, fibrin monomers, and fibrinogen were also similar for both regimen, and there was a significant difference in tPA-PAI1 complex concentrations at the end of surgery, which may be related to a significantly higher tranexamic acid concentration. Continuous and discontinuous regimen are suitable for an effective inhibition of fibrinolysis in children undergoing cardiac surgery with CPB, but the continuous regimen was previously shown to be more effective to maintain stable tranexamic acid concentrations.
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Comparison of different doses of -aminocaproic acid in children for tetralogy of fallot surgery: clinical efficacy and safety
Sarupria A, Makhija N, Lakshmy R, Kiran U
Journal of Cardiothoracic & Vascular Anesthesia. 2013;27((1):):23-9.
Abstract
OBJECTIVE The purpose of this study was to compare 2 different doses of -aminocaproic acid (EACA) and assess their relative efficacy and safety in children undergoing corrective surgery for tetralogy of Fallot (TOF). DESIGN A prospective, randomized, controlled study. SETTING A tertiary care center. PARTICIPANTS One hundred twenty children undergoing corrective surgery for TOF using cardiopulmonary bypass (CPB). INTERVENTIONS Group 1 received 100 mg/kg of EACA after induction, upon initiation of CPB, and after protamine. Group 2 received 75 mg/kg of EACA after induction, followed by a maintenance infusion of 75 mg/kg/h until chest closure, and an additional 75 mg/kg upon initiation of CPB. Group 3 did not receive any antifibrinolytic agent or placebo. MEASUREMENT AND MAIN RESULTS Cumulative mean blood loss, total packed red blood cells, and fresh frozen plasma requirements were significantly less in group 2 (p <= 0.01). There were no significant differences in the total platelet concentrate transfused, re-exploration rate, incidence of renal failure, arrhythmias, neurologic complications, mortality, or length of intensive care unit stay among the 3 groups. The incidences of perioperative ST/T changes and chest closure time were significantly less in group 1 and group 2 (p <= 0.01). The duration of mechanical ventilation was significantly less in group 2 (p <= 0.01). CONCLUSIONS EACA was effective in reducing the postoperative blood loss and transfusion requirements in children undergoing corrective cardiac surgery on CPB for TOF. The dose regimen of 75 mg/kg after induction, followed by a maintenance infusion of 75 mg/kg/h until chest closure, and an additional 75 mg/kg upon initiation of CPB were more effective. Copyright 2012 Elsevier Inc. All rights reserved.