Children undergoing major surgery are frequently exposed to a high risk of perioperative bleeding with concomitant requirement of blood product transfusion. This increases the risk of postoperative adverse outcomes, resulting in longer length of hospital stay and increased morbidity and mortality.1 The underlying mechanisms that increase the bleeding risk differ depending on the type of surgery performed. For example, our main experience comes from children undergoing cardiac surgery with cardiopulmonary bypass (CPB). In this setting, CPB causes various hemostatic derangements, including hemodilution due to the administration of a large amount of fluid through the priming solution. Nonphysiological contact between blood, nonendothelial surfaces, and air can activate coagulopathy, and tissue injury and activation of the hemostatic process during surgery can generate consumption coagulopathy.2 The mechanisms will be different in other major settings, such as scoliosis surgery, major orthopedic surgery, or craniofacial surgery.
Activation of the fibrinolytic system, leading to conversion of the inactive substrate plasminogen to plasmin, is a major component of the vascular hemostatic mechanisms to maintain vascular patency. Multiple pathways can activate plasmin generation, including endothelial activation, contact activation, and kallikrein-mediated plasmin activation.3 These physiologic mechanisms help maintain equilibrium between clot formation and clot lysis, avoiding thrombosis remote from sites of injury. In cases of trauma or major surgery, extensive tissue injury produces large amounts of tissue activators (tissue plasminogen activator, urokinase, and kallikrein) leading to a shift from physiological fibrinolysis to hyperfibrinolysis.4 In addition, plasmin induces many other responses that contribute to coagulopathy and bleeding, including activation of thrombin generation, cleavage of fibrinogen to fibrin, and cleavage of receptors on platelets.5 This hyperfibrinolysis decreases clot stability and increases bleeding tendency, which subsequently increases coagulopathy, fibrinogen, and clot factor consumption. Together, these steps can place children having major surgery in the middle of a vicious circle (Fig. 1).
Antifibrinolytic drugs are being used more frequently in our daily practice to decrease fibrin degradation through inhibition of plasmin generation and therefore to decrease blood loss and transfusion requirements in different types of major surgeries.6 Before 2008, the most commonly used antifibrinolytic drug was aprotinin, a nonspecific serine protease inhibitor derived from bovine lung.7 Due to safety concerns in high-risk adults undergoing cardiac surgery with CPB, aprotinin is no longer available in most countries and has been replaced by lysine analogs.8,9 Tranexamic acid (TXA) and ε-aminocaproic acid (EACA) are synthetic lysine analogs that competitively inhibit the activation of plasminogen to plasmin.10 TXA is the most common antifibrinolytic used worldwide because EACA is not available in many countries such as Canada, New Zealand, and most of Europe. The results of randomized controlled trials and systematic reviews support the use of lysine analogs to decrease blood loss and transfusion requirements in adults undergoing cardiac11 and orthopedic surgery,12 in adult trauma patients,13 as well as in children.6,14,15
The present systematic review discusses the current literature regarding the efficacy of the antifibrinolytic lysine analogs in children undergoing major noncardiac surgery. Figure 2 is a flowchart that details the different steps of our systematic review. We have performed an exhaustive literature search using MEDLINE and EMBASE (using “AND” and “OR”) with the following Boolean operators: lysine analogs, tranexamic acid, epsilon aminocaproic acid, antifibrinolytics, children, pediatrics, spinal surgery, scoliosis surgery, craniofacial surgery, trauma, and massive bleeding. The operator was defined as MeSH without quotation marks. No restriction was made regarding the date of publication, and only articles written in English were included in our selection. Primary selection was performed by DF and then reviewed by SMG. The authors then screened the literature again to make ensure that no study had been missed. Throughout this article, exact P values, obtained from the original study, are reported. We used P < 0.01 or P < 0.001 when it appeared in the original study. All articles relating to the use of the antifibrinolytic drugs (TXA and EACA) in children undergoing major surgery, including orthopedic, spinal, or craniofacial surgeries, were included. Because Aprotinin has limited availability worldwide, we voluntarily excluded studies using aprotinin in the treatment group and focused on prospective trials, retrospective studies, and meta-analyses that evaluated the efficacy of lysine analogs in noncardiac major surgeries, with particular attention paid to studies that evaluated the pharmacokinetic (PK) profile of TXA and EACA in these different settings. Coagulopathy induced during cardiac surgery is a specific condition unique to cardiac surgery which includes contact activation due to CPB, hemodilution secondary to CPB prime, the presence of a cyanogen disease, the complexity of the surgical procedure, etc.16 For these reasons, and the fact that this topic was adequately discussed in other systematic reviews,6,14,15 we voluntarily excluded studies performed in the cardiac setting from our systematic review and focused on noncardiac use of antifibrinolytic drugs.
ANTIFIBRINOLYTICS IN SCOLIOSIS SURGERY
Scoliosis is a musculoskeletal disorder in which children present with complex structural deformities of the spine and with abnormal curvature of the vertebral column in all 3 axes. There are multiple etiologies: idiopathic, congenital, neurological, or secondary to musculoskeletal disorders.17 Early orthopedic and surgical treatment decreases progression of the deformities and improves the child’s development.
Despite progress made in surgical techniques, scoliosis surgery remains associated with major complications, including excessive blood loss and major transfusion requirements. Several factors have been implicated in the etiology of increased blood loss, including neuromuscular etiology, weight and height of the patient, poor nutritional status, severity of spinal deformity, number of spinal segments fused, surgical complexity including reoperation and more complex anterior/posterior approach, intraoperative arterial blood pressure control, and dilutional coagulopathy.18 Furthermore, this type of surgery requires significant tissue/bone dissection and prolonged operating times, which can lead to fibrinolysis activation, major blood loss (from 500 to >2500 mL), and coagulopathy.
A recent survey of UK practices reported wide variations in blood conservation strategies in children undergoing scoliosis surgery.19 They found that 81% of the screened centers routinely used antifibrinolytic drugs (all of which used TXA). However, there was a huge variation among dosage schemes, with initial loading doses varying between 2 and 100 mg/kg, sometimes followed by a continuous infusion of between 3 and 10 mg/kg/h.
In the present systematic review, we identified 13 relevant prospective or retrospective studies that evaluated the efficacy of lysine analogs during pediatric and adolescent scoliosis surgery. Table 1 summarizes the studies that compared treatment with EACA with no treatment, while Table 2 summarizes the trials that compared treatment with TXA with placebo or alternative treatments. In 2001, Florentino-Pineda et al.20 published a preliminary, prospective, nonrandomized study that evaluated the efficacy of EACA in children with idiopathic scoliosis undergoing posterior spinal fusion. They compared the perioperative blood loss between 28 children who received EACA and 31 children who did not and found that intraoperative (P = 0.024), postoperative (P = 0.003), and total estimated blood loss (P = 0.003) were decreased in children treated with EACA. Transfusion requirements were also decreased in the treated group (P = 0.003 for the total number of units given). The same team confirmed these results in a small prospective trial that included 36 patients randomized between the EACA (n = 19) and control (n = 17) groups.21 In 2005, the same group further assessed the effects of EACA on blood loss reduction with the EACA administered during the anterior time of the surgery compared with during both anterior and posterior spinal fusion, and they evaluated the effects of EACA on postoperative fibrinogen levels.22 However, the disparity between the different study groups and the complexity of the study design did not allow the authors to draw relevant conclusions regarding EACA efficacy and effects on fibrinogen levels.
More recently, Thompson et al.23,24 published 2 retrospective studies showing that, regardless of the conditions of administration, EACA decreased blood loss and transfusion requirement. It is important to note that the same team performed these studies, and some data were used in different publications. For this reason, the only dosage scheme assessed in the EACA studies comprised an initial loading dose of 100 mg/kg, followed by a continuous infusion of 10 mg/kg/h until the end of the surgery.
The studies pertaining to EACA use in scoliosis surgery are summarized in Figure 3, A (blood loss) and B (blood transfusion).
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).
The studies pertaining to TXA use in scoliosis surgery are summarized in Figure 4, A (blood loss) and B (blood transfusion)
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.
ANTIFIBRINOLYTICS IN CRANIOFACIAL SURGERY
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 April 2011 issue of Anesthesiology included 2 prospective, randomized, controlled trials that evaluated the efficacy of TXA for reducing the need for blood transfusion in children undergoing craniofacial surgery (Table 2).33,34 In the first study, 40 consecutive children were randomized to receive either TXA (15 mg/kg over 15 minutes followed by 10 mg/kg/h) or saline.33 In addition, all children were preoperatively treated with iron and had 3 treatments with 600 U/kg recombinant human erythropoietin. In the TXA group, fewer children required transfusion (36.8% in the TXA group vs 70% in the control group, P = 0.04), and fewer RBCs were transfused (7.2 vs 16.6 mL/kg, P = 0.03). In the second study, 43 children aged 2 months to 6 years were randomized to receive either TXA (50 mg/kg over 15 minutes followed by 5 mg/kg/h) or saline.34 It was found that, compared with the control group, the TXA group exhibited decreased blood loss (119 vs 65 mL/kg, P < 0.001), decreased amount of RBCs transfused (56 vs 33 mL/kg, P = 0.006), decreased number of RBC units administered (from 3 to 1 U), and a reduction in the use of fresh frozen plasma. Both studies showed that implementation of a patient blood management strategy involving prophylactic TXA administration is useful for decreasing blood loss and transfusion requirement in children undergoing craniofacial surgery.
In the editorial published with these 2 studies, Holcomb44 states that several questions remain unanswered. First, defining the optimal dose of TXA will require a PK evaluation in children undergoing craniofacial surgery. Second, the sensitivity of point-of-care monitoring (thromboelastography [TEG®], Hemostasis system, Haemoscope Corporation, Niles, IL; rotational thromboelastometry [ROTEM®], TEM® International GmbH, Munich, Germany) for hyperfibrinolysis detection is unknown. Sophisticated measures of fibrinolysis should be used to assess the degree of fibrinolysis and concentration that is necessary for TXA to adequately inhibit fibrinolysis.
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.
TRAUMA OR MASSIVE BLEEDING IN CHILDREN
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.
Name: David Faraoni, MD, FCCP.
Contribution: This author helped design the study, searched the literature, performed the analyses, and wrote the manuscript.
Attestation: David Faraoni approved the final manuscript.
Name: Susan M. Goobie, MD, FRCPC.
Contribution: This author helped design the study, searched and reviewed the literature, helped write the manuscript, and reviewed the manuscript.
Attestation: Susan M. Goobie approved the final manuscript.
This manuscript was handled by: Peter J. Davis, MD.
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