We also identified 8 studies in which TXA was administered in children undergoing scoliosis surgery.25–32 Of these trials, only 3 were prospective, randomized, and controlled.25,26,32 In the first, Neilipovitz et al.25 prospectively randomized children scheduled for scoliosis surgery to receive either 10 mg/kg TXA followed by a continuous infusion of 1 mg/kg/h, or the same infusion scheme with saline. They demonstrated that the TXA-treated patients had smaller total perioperative blood requirements (P = 0.045), but volumes of red blood cells (RBCs) administered were not statistically different. In the second study, Sethna et al.26 randomly allocated patients into a TXA or control group. TXA was administered using an initial loading dose of 100 mg/kg followed by continuous infusion of 10 mg/kg/h. They observed that TXA administration significantly decreased the total blood loss (P < 0.01); however, transfusion requirement was not significantly decreased. Finally, Xu et al.32 randomized 80 adolescent patients scheduled for idiopathic scoliosis surgery to receive TXA (20 mg/kg followed by 10 mg/kg/h), normal saline, batroxobin (0.02 U/kg), or a combination of both. Batroxobin is a thrombin-like enzyme derived from the venoms of reptile described as Bothrops atrox moojeni. The enzyme clots plasma by converting fibrinogen to fibrin with the release of only fibrinopeptide.35 The authors observed that TXA and batroxobin can markedly reduce blood loss and transfusion requirements (P < 0.001), but TXA performed better in minimizing fresh frozen plasma transfusion (P = 0.025) and the overall drainage than batroxobin (P < 0.001).
In summary, antifibrinolytics seem effective at decreasing blood loss and blood transfusion in pediatric scoliosis surgery, but these data are from small, single-center, prospective or retrospective studies. There are several criticisms regarding the available literature on the safety of antifibrinolytics in children undergoing scoliosis surgery. First, since data about TXA and EACA come from retrospective or small prospective trials (some even nonrandomized and nonblinded), none of the published trials were designed and adequately powered to observe significant differences in terms of side effects, which is an important concern since data from pediatric cardiac surgery indicate that TXA is associated with an increased incidence of seizures.36 These limitations have already been highlighted by 2 systematic reviews with meta-analysis.37,38 A large variability in dosage schemes was observed among the different studies with no rationale for using specific doses. In addition, the dosage schemes used in these trials are not based on PK studies; in fact, the PK profile of antifibrinolytic drugs has not yet been assessed in the pediatric orthopedic population. Furthermore, the effective TXA therapeutic plasma level to be targeted to inhibit fibrinolysis is not even known in this setting. It is crucial to note that the best benefit-to-risk balance will be reached only when physicians have the information necessary to administer the right amount of antifibrinolytics, to the right children, and during the right period. For these reasons, further studies are needed to assess the PK profile of children undergoing idiopathic and secondary scoliosis surgery. Two trials are currently underway for TXA (ClinicalTrials.gov NCT01813058) and EACA (ClinicalTrials.gov NCT01408823). The results of these studies will be of benefit in future research in evaluating the best dosage scheme to decrease hyperfibrinolysis, blood loss, and transfusion requirements.
Craniosynostosis is a relatively common disease that arises from premature bony cranial fusion and is accompanied by skull volume restriction. In the general population, this pathology occurs with an incidence of about 1 infant per 1800 births.39 Surgical correction to expand and remodel the cranium in early infancy is recommended to prevent intracranial hypertension, cerebral compression, and blindness. Surgical correction is also performed to normalize skull shape and improve appearance because not all infants are at risk for these complications. This extensive procedure is associated with considerable blood loss and transfusion requirements.40 Well-defined, intraoperative, multimodal patient blood management protocols are needed to reduce blood loss, transfusion of blood and blood products, and their associated comorbidity.41 These protocols should include a combination of modalities including preoperative optimization, intraoperative blood cell salvage techniques, topical drugs, and improvements in surgical technique. Preoperative supplementation with iron and/or recombinant human erythropoietin may be helpful, but further studies are needed to assess the real benefit-to-risk balance.42 The use of antifibrinolytic drugs has been recommended to reduce blood loss and transfusion requirement in this high-risk population.43
The first question is now partially answered since the publication of the first population PK study in children undergoing craniofacial surgery.45 This study described TXA PK as a 2-compartment open model with systemic clearance influenced by age and total body weight. Based on this study and the presumed minimal therapeutic plasma level of 16 μg/mL, an initial loading dose of 10 mg/kg administered over 15 minutes followed by continuous infusion of 5 mg/kg/h was determined to be optimal to reach and maintain steady state during craniofacial surgery. In a second population PK study, Stricker et al.46 evaluated the PK profile of EACA in infants undergoing craniofacial surgery. This study used 3 dose schemes (25 mg/kg followed by continuous infusion of 10 mg/kg/h, 50 mg/kg followed by 20 mg/kg/h, and 100 mg/kg followed by 40 mg/kg/h). Based on their results, the authors recommended an initial loading dose of 100 mg/kg followed by a continuous infusion of 40 mg/kg/h. These 2 trials represent significant progress in evaluating the use of antifibrinolytic drugs in children undergoing craniofacial surgery. Further studies are needed to assess the pharmacodynamic profile according to the recommended schemes.
Experience with adults has shown hyperfibrinolysis to be a major component of trauma-induced coagulopathy (TIC).47 Tauber et al.48 recently reported that 6.8% of traumatized patients develop a significant degree of hyperfibrinolysis as evaluated by ROTEM. In another study, Theusinger et al.49 showed that hyperfibrinolysis and its severity are associated with poor outcomes in both traumatized and nontraumatized patients. Trauma-induced hyperfibrinolysis has never been evaluated in the pediatric population. TIC was described in a pediatric population as early as 1982 by Miner et al.50; however, no further study was performed to assess the consequences of TIC or incidence of coagulopathy in children.
One large prospective trial (CRASH 2, Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage) studied early TXA administration in traumatized adult patients.13 The authors observed that early administration of 1 g TXA followed by infusion of an additional 1 g over 8 hours safely reduced the risk of death in bleeding trauma patients. Unfortunately, there is no similarly well-designed trial for the pediatric population, and there are currently no available data regarding systematic use of TXA in a traumatized child. However, in a November 2012 evidence statement titled Major Trauma and the Use of Tranexamic Acid in Children, the Royal College of Paediatrics and Child Health and the National and Paediatric Pharmacists Group Joint Committee recommended a pragmatic dosage schedule of 15 mg/kg initial loading dose (maximum 1 g) over 10 minutes followed by 2 mg/kg/h.
In addition, only sparse data have been published pertaining to the use of antifibrinolytic drugs during transplantation. It is important to note here that there are significant concerns regarding antifibrinolytic therapy in children undergoing orthotopic liver transplantation that may differ significantly from adults. Despite a small retrospective study showing no increase in early arterial thrombosis in adults who received antifibrinolytics,51 the incidence of early arterial thrombosis is higher in children and occurs much earlier in the postoperative course as compared with adults.52
Until a well-designed study is performed, no safe recommendations can be formulated.
Reducing blood loss and blood transfusion profoundly impacts health care worldwide by significantly decreasing morbidity and mortality, decreasing costs, and improving health care for infants and children undergoing major surgery involving significant blood loss.
The American Medical Association and the Joint Commission’s September 2012 National Summit on Overuse identified blood transfusion as one of the 5 most important health care–related overuse issues in the world today. Furthermore, the World Health Organization (World Health Organization resolution WHA63.12) in May 2012 recommended patient blood management strategies as important in the care of surgical patients worldwide. However, there are very few reports in the literature regarding implementing this technique. We have summarized the use of inexpensive, readily available, and easy to administer antifibrinolytic medications, TXA and EACA, which have proven safety profiles in other surgical populations (e.g., adults undergoing CPB). The use of these drugs during pediatric surgery is an important part of a comprehensive patient blood management strategy. Further investigations of the efficacy, safety, appropriate dosing scheme, and PK profile in children will have a positive impact on patient care nationally and internationally.
As discussed in this review, the information available in the current literature is limited. Even when children undergoing scoliosis surgery successfully receive treatment with an antifibrinolytic drug, the doses used are not based on PK data. Further prospective, randomized, controlled trials are clearly needed to assess the efficacy of TXA for reducing perioperative blood loss in this population (ClinicalTrials.gov NCT01813058). In addition, the PK profile must be assessed and viewed in relation to pharmacodynamic data such as efficacy in the reduction of blood loss and blood transfusion and in evaluating the effects of antifibrinolytics on the biologic variables of fibrinolysis. Goobie et al.34 demonstrated that clinical efficacy was shown despite the absence of demonstrable changes in TEG®.
Nevertheless, the sensitivity of ROTEM® or TEG® to detect hyperfibrinolysis is not well known,53 as observed in different studies.45,54 Furthermore, the exact mechanisms leading to activation of the fibrinolytic pathway are not well known. Future studies should assess the degree of hyperfibrinolysis needed to observe a significant increase in perioperative blood loss. Finally, it is possible that lysine analogs may have effects beyond fibrinolysis itself. Jimenez et al.55 showed that inflammatory markers, d-dimers, and plasminogen activator inhibitor-1 were significantly lower with TXA than placebo and concluded that TXA influences the degree of systemic inflammation associated with cardiac surgery. Weber et al.56 proposed that TXA might be a pharmacological option to partially increase platelet aggregation in patients treated with dual antiplatelet therapy. Finally, no published study has been sufficiently powered to adequately assess the safety profile of these drugs. Indeed, experience from children with congenital heart disease highlights that high-dose lysine analogs administration could be associated with an increased risk of seizures.57 Fortunately, no similar observation has been found either in scoliosis or craniofacial surgeries. Furthermore, larger prospective trials are needed to better define the safety profile of these drugs.
In conclusion, the use of antifibrinolytic drugs appears to significantly decrease blood loss and transfusion requirement in children undergoing major orthopedic or craniofacial surgery. Although there is increasing information in the literature about PK assessment, further prospective trials are needed to better define the best dose scheme and the safety profile of these drugs. Administration of TXA or EACA could potentially be helpful in other settings, such as transplantation, trauma, or massively bleeding children.
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