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Efficacy and Safety of Antifibrinolytic Drugs in Pediatric Surgery: A Systematic Review
Hovgesen NT, Larsen JB, Fenger-Eriksen C, Hansen AK, Hvas AM
Seminars in thrombosis and hemostasis. 2021;47(5):538-568
Abstract
Antifibrinolytic drugs are used to reduce blood loss and subsequent transfusions during surgery and following trauma, but the optimal dosing regimen in the pediatric population is still unresolved. The aim of this systematic review was to evaluate efficacy and safety of antifibrinolytic drugs in pediatric surgery and trauma to determine the optimal dosing regimen. A literature search was performed in PubMed, Embase, Cochrane, and Web of Science on May 3, 2020. We included randomized controlled studies investigating the effect of tranexamic acid (TXA), aprotinin, and epsilon-aminocaproic acid, in terms of reducing blood loss, blood transfusions, reoperations, and rebleeds in pediatric patients aged 0 to 18 years undergoing cardiac surgery, noncardiac surgery, or trauma. Fifty randomized controlled trials (RCTs) were included; 28 RCTs investigated cardiac surgery and 22 investigated noncardiac surgery. No RCTs regarding trauma met the inclusion criteria. All antifibrinolytic drugs reduced postoperative blood loss and transfusions when used in pediatric surgery. The dosing regimen varied between studies, but similar effect sizes were found in terms of reduced blood loss regardless of the cumulative dose used. Few studies found adverse events, and no difference in incidence or type of adverse events was seen between the antifibrinolytic and the placebo group. In conclusion, use of antifibrinolytics is efficient and safe in children undergoing surgery. We propose TXA as the drug of choice based on its level of evidence and safety profile; we recommend a dosing regimen composed of a loading dose of 10 to 15 mg/kg prior to surgery followed by 1 to 5 mg/kg/h as continuous infusion throughout surgery.
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Effect of tranexamic acid on markers of inflammation in children undergoing craniofacial surgery
Fenger-Eriksen C, Rasmussen M, Juul N, Krog J, Hvas AM
Acta anaesthesiologica Scandinavica. 2020
Abstract
BACKGROUND Tranexamic acid (TXA) reduces blood loss and transfusion requirements during craniosynostosis surgery in small children. Possible interaction from TXA on the inflammatory system is unknown. OBJECTIVE To evaluate the effect of TXA on a wide range of inflammatory markers in children receiving TXA in a randomized, blinded and placebo controlled study design. METHODS Thirty children undergoing craniosynostosis surgery with significant blood loss received TXA (bolus dose of 10 mg kg(-1) followed by 8 hours continuous infusion of 3 mg kg(-1) h(-1) ) or placebo in a randomized, double-blinded study design. Using a new proximity extension assays employing a panel of inflammatory biomarkers samples was used for analysis of blood samples obtained preoperatively, 4h and 24 h after operation. RESULTS Ninety-two inflammatory parameters were measured. TXA did not affect any of the measured parameters as compared with placebo. Among 34 of the 92 pro- and antiinflammatory parameters investigated changes were observed between preoperative, 4 h or 24 h respectively, reflecting immune activation during surgical stress. CONCLUSION TXA administration in a low-dose regimen including bolus followed by 8h infusion during craniosynostosis surgery did not change any of 92 inflammatory markers as compared with placebo.
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Effect of Tranexamic Acid on Coagulation and Fibrin Clot Properties in Children Undergoing Craniofacial Surgery
Fenger-Eriksen C, Lindholm AD, Krogh L, Hell T, Berger M, Hermann M, Fries D, Juul N, Rasmussen M, Hvas AM
Thrombosis and haemostasis. 2020
Abstract
OBJECTIVE Craniosynostosis surgery in small children is very often associated with a high blood loss. Tranexamic acid (TXA) reduces blood loss during this procedure, although the potential underlying coagulopathy in these children is not known in detail. Objective was to determine the nature of any coagulopathy found during and after craniosynostosis surgery and to characterize the effect of TXA on fibrin clot formation, clot strength, and fibrinolysis. MATERIALS AND METHODS Thirty children received either TXA (bolus dose of 10 mg/kg followed by 8 hours continuous infusion of 3 mg/kg/h) or placebo. Dynamic whole blood clot formation assessed by thromboelastometry, platelet count, dynamic thrombin generation/thrombin-antithrombin, clot lysis assay, and fibrinogen/factor XIII (FXIII) levels were measured. Additionally, clot structure was investigated by real-time live confocal microscopy and topical data analysis. RESULTS Increased ability of thrombin generation was observed together with a tendency toward shortened activated partial thromboplastin time and clotting time. Postoperative maximum clot firmness was higher among children receiving TXA. FXIII decreased significantly during surgery in both groups.Resistance toward tissue plasminogen activator-induced fibrinolysis was higher in children that received TXA, as evidenced by topical data analysis and by a significant longer lysis time. Fibrinogen levels were higher in the TXA group at 24 hours. CONCLUSION A significant coagulopathy mainly characterized by changes in clot stability and not parameters of thrombin generation was reported. Tranexamic acid improved clot strength and reduced fibrinolysis, thereby avoiding reduction in fibrinogen levels.
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The Role of Platelets in Premature Neonates with Intraventricular Hemorrhage: A Systematic Review and Meta-Analysis
Grevsen AK, Hviid CVB, Hansen AK, Hvas AM
Seminars in thrombosis and hemostasis. 2019
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Editor's Choice
Abstract
Intraventricular hemorrhage (IVH) affects up to 22% of extremely low birth weight neonates. Impaired coagulation might contribute to the pathogenesis of IVH. The aims of this study were to summarize the current knowledge on the role of platelet indices in premature neonates with IVH and to provide an overview of secondary hemostasis parameters as well as fibrinolysis in premature neonates with IVH. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, Scopus, and Web of Science were searched on March 7, 2019, without time restrictions. In total, 30 studies were included. Most studies investigated the significance of platelet counts and/or mean platelet volume (MPV). The meta-analysis showed that at day 1 of life, neither platelet count nor MPV differed significantly between neonates with or without IVH (standardized mean difference [SMD]: -0.15 x 10(9)/L, 95% confidence interval [CI]: -0.37 to 0.07 and SMD: 0.22 fl, 95% CI: -0.07 to 0.51, respectively). However, platelet counts < 100 x 10(9)/L were associated with an increased risk of IVH. Secondary hemostasis parameters did not differ between neonates with and without IVH. Fibrinolysis was only sparsely investigated. In conclusion, platelet counts < 100 x 10(9)/L were associated with an increased risk of IVH in premature neonates. The impact of secondary hemostasis was only sparsely investigated but seemed to be minor, and the role of fibrinolysis in IVH in premature neonates needs further research. Whether reduced platelet function is associated with an increased risk of IVH in premature neonates remains to be investigated.
PICO Summary
Population
Extremely low birth weight neonates (30 studies).
Intervention
Platelet indices in neonates with IVH.
Comparison
Platelet indices in neonates without IVH.
Outcome
The meta-analysis showed that at day 1 of life, neither platelet count nor MPV differed significantly between neonates with or without IVH. However, platelet counts < 100 x 10(9)/L were associated with an increased risk of IVH. Secondary hemostasis parameters did not differ between neonates with and without IVH. Fibrinolysis was only sparsely investigated.
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Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial
Fenger-Eriksen C, D'Amore Lindholm A, Norholt SE, von Oettingen G, Tarpgaard M, Krogh L, Juul N, Hvas AM, Rasmussen M
British journal of anaesthesia. 2019
Abstract
BACKGROUND Tranexamic acid (TXA) reduces intraoperative blood loss and transfusion during paediatric craniosynostosis surgery. Additional reduction of postoperative blood loss may further reduce exposure to allogeneic blood products. We studied the effect of combined intra- and postoperative TXA treatment on postoperative blood loss in children. METHODS Thirty children admitted for craniosynostosis surgery were randomised to combined intra- and postoperative TXA treatment or placebo. The primary endpoint was postoperative blood loss. Secondary endpoints included total blood loss, transfusion requirements, and clot stability evaluated by tissue plasminogen activator-stimulated clot lysis assay. RESULTS TXA reduced postoperative blood loss by 18 ml kg(-1) (95% confidence interval 8.9) and total blood loss from a mean of (standard deviation [SD]; 20) ml kg(-1) to 28 (14) ml kg(-1) (P<0.001). Intraoperative red blood cell (RBC) and fresh frozen plasma (FFP) transfusions were reduced in the treatment group from RBC 14.0 (5.2) ml kg(-1) to 8.2 (5.1) ml kg(-1) (P=0.01) and from FFP 13.0 (6.3) ml kg(-1) to 7.8 (5.9) ml kg(-1) (P=0.03). Postoperative RBC transfusion median was 5 (inter-quartile range [IQR] 0-6) ml kg(-1) in the placebo group and 0 (0-5.7) ml kg(-1) in the TXA group. Resistance to lysis was higher in the treatment group (P<0.001). CONCLUSIONS Combined intra- and postoperative tranexamic acid treatment reduced postoperative and overall blood loss and transfusion requirements. Improved clot stability represents a possible mechanism for blood loss reduction.