Cardiopulmonary bypass (CPB) profoundly alters hemostasis, increasing the risk of bleeding and the transfusion requirement. The pediatric population, particularly neonates, is at high risk for major complications, given their relatively immature hemostatic system, the complexity of the surgeries performed, and the high ratio of the total blood volume to the amount of fluids added in the CPB prime.1 Bleeding prevention should be considered on a patient-based multimodal approach, and it is now accepted that antifibrinolytic agents may play a central role in perioperative bleeding prophylaxis in both adults and children.
Tranexamic acid (TXA) is routinely used in children undergoing cardiac surgery, and several trials have shown that the drug significantly decreases blood loss and transfusion requirements when administered in the perioperative period.2 On the contrary, administration of antifibrinolytic agents is associated with potential side effects.3 Recent studies compared the safety of TXA with aprotinin4 and epsilon aminocaproic acid (EACA).5 The following incidences were reported in children receiving TXA: renal injury, 9.6%; renal failure, 1.8%; seizures, 3.5%; and other neurological events, 2.6%. The side effects associated with the administration of TXA and EACA are dose dependent.6 For these reasons, the benefit-to-risk balance should be assessed and an optimal dosing scheme based on the minimally effective therapeutic plasma concentration of TXA, that is, the dosage scheme with the best reduction of blood loss and fewest side effects should be considered.
In a recent systematic review with meta-analysis, a large amount of variability was observed in dose regimens among trials.7 Some studies used a single bolus ranging from 10 to 100 mg/kg.8–10 Others used repeated boluses at anesthesia induction, in the CPB prime, and after protamine administration.8,11–13 Finally, other studies described a continuous infusion during and/or after CPB.8,14,15 Several factors may explain the high degree of heterogeneity observed among the studies. First, the TXA dosage regimes were not based on pharmacokinetic (PK) principles. In fact, the TXA PK parameters in this population were unknown until the recent publication of the first population PK study in children undergoing craniofacial surgery,16 which was followed by a second study in children undergoing cardiac surgery.17 In this second study, Grassin-Delyle et al.17 randomized 21 children, aged between 1 and 12 years (weight: 10–30 kg), to receive TXA either continuously (10 mg/kg followed by 1 mg/kg/h) or using repeated boluses (10 mg/kg after anesthesia induction, 10 mg/kg during the CPB, and 10 mg/kg at the end of the CPB). The PK of TXA in children were best described by an open 2-compartmental model with linear elimination. A dosing scheme for optimized TXA administration in those children was proposed; however, it used a target concentration of TXA based on in vitro data established using adult plasma as the therapeutic concentration. No study has assessed the therapeutic concentration of TXA needed to prevent fibrinolysis since the paper published by Andersson et al.18 in 1968. Consequently, no ideal dose scheme could be proposed.
In 2010, Yurka et al.19 determined the minimum effective concentration of EACA for inhibition of in vitro fibrinolysis induced by tissue-type plasminogen activator (tPA) in neonatal plasma derived from cord blood. They observed that the minimally effective concentration was significantly lower in neonatal plasma than in adult plasma.19 This concentration was significantly lower than the concentration targeted by current dosing schemes, indicating that neonates are possibly being exposed to greater levels of EACA than necessary.
In this issue of Anesthesia & Analgesia, Yee et al.20 publish the results of a study using the same model as Yurka et al.19 to assess the minimal concentration of TXA needed to completely inhibit hyperfibrinolysis. They used neonatal plasma samples derived from cord blood from 20 term cesarean deliveries. Hyperfibrinolysis was induced by tPA, and graded concentrations of TXA were added to the pooled plasma. Thromboelastography (TEG®, Hemostasis system, Haemoscope Corporation, Niles, IL) was used to assess clot firmness and fibrinolysis. They found that neonatal plasma required significantly lower TXA concentrations to completely prevent hyperfibrinolysis than adult plasma (6.54 μg/mL [95% confidence interval, 5.19–7.91] vs 17.5 μg/mL [95% confidence interval, 14.59–20.41]). This work could serve as a basis for future studies to precisely evaluate the best TXA dosing scheme and the benefit-to-risk balance of TXA in these children.
Even after the recent publications, the ideal dose regimen remains undetermined. The population PK study published by Grassin-Delyle et al.17 was performed in children aged >1 year and cannot be generalized to the whole pediatric population. Additional studies are still required in neonates and children aged <1 year or weighing <10 kg. In addition, Yee et al.20 determined the targeted TXA concentration in cord blood after in vitro activation by tPA in a very high concentration (1000 units/mL). It is not clear how this compares with in vivo activation of fibrinolysis during surgery and CPB, in which significantly lower concentrations of tPA have been reported.21
In the last few years, a number of studies have tried to assess the influence of hyperfibrinolysis on increased bleeding, particularly during cardiac surgery with CPB. This procedure is associated with increased fibrinolytic activity and increased concentrations of circulating tPA and plasminogen activator inhibitor type-1 (PAP-1), which block the conversion of plasminogen to plasmin, thus promoting hyperfibrinolysis. However, hyperfibrinolysis and its underlying mechanisms are not perfectly understood. Moreover, interindividual variations in plasmatic fibrinolytic markers are large. In addition, confounding factors may increase the risk of hyperfibrinolysis perioperatively in cardiac surgery with CPB.22 Thus, considering this inherent variability in the degree of hyperfibrinolysis with CPB, further evaluation of TXA is necessary in this setting.
Finally, it is still not clear which tests are best for assessing fibrinolysis. Screening laboratory tests of coagulation (partial thromboplastin time, prothrombin time, etc.) do not assess fibrinolysis; solely measuring d-dimer levels gives an incomplete picture and other tests are not routinely performed (e.g., euglobulin lysis time, PAP complex). Monitoring by TEG® or rotational thromboelastometry (ROTEM®; TEM® International GmbH, Munich, Germany) is increasingly used, but the sensitivity of these tests to detect fibrinolysis remains undetermined. While ROTEM could be used to detect severe hyperfibrinolysis and guide the therapeutic approach in particular clinical settings,23 Raza et al.24 observed that fibrinolysis detected by the PAP complex and d-dimer determination was not systematically detected by conventional ROTEM. Thus, further studies are needed to better define the incidences of fibrinolysis in children undergoing cardiac surgery using both ROTEM and laboratory tests.
In summary, the article published by Yee et al.20 in this issue of Anesthesia & Analgesia is a significant but small piece of the puzzle that will lead a better use of TXA in children undergoing cardiac surgery. Further studies are still required to assess the PK profile in different age groups having different surgeries and to better define the optimum therapeutic plasma concentration of TXA needed to safely inhibit fibrinolysis in the perioperative period. This ideal dosing scheme should provide an optimal TXA plasma concentration to decrease blood loss and the transfusion requirement without increasing side effects. Ultimately, what will be needed are 1 or more clinical studies using PK/pharmacodynamic-derived dosing schemes on neonates and older children to confirm that the schemes are safe and effective.
Name: David Faraoni, MD, FCCP.
Contribution: This author wrote the manuscript and approved the final version of the manuscript.
Attestation: This author approved the final manuscript.
Name: Susan M. Goobie, MD, FRCPC.
Contribution: This author helped write the manuscript, reviewed the manuscript, and approved the final version.
Attestation: This author approved the final manuscript.
This manuscript was handled by: Jerrold H. Levy, MD, FAHA, FCCM.
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