Discussion
Children undergoing surgical correction of craniosynostosis often experience high rates of bleeding and a type of controlled traumatic coagulopathy for which the mechanisms and optimal interventions are currently unknown.3,20,21 Antifibrinolytic therapy has been proven to be efficacious in reducing blood loss and need for transfusion in this population, but the relative efficacy of EACA vs. TXA is unknown.17,19,22,23 Likewise, the optimal dosing and duration of antifibrinolytic therapy remain unknown.14,23 The primary goal of this study was to compare the rates of blood loss and transfusion in children receiving EACA vs. TXA. At our institution, there was a transition in type of antifibrinolytic agent used from EACA to TXA at the end of 2017, which was primarily based on drug availability. Other factors, including surgeons and anesthesia protocols, remained equal across that time period. In our cohort, we did not find any significant difference in blood loss, transfusion requirements, hematologic parameters, or adverse outcomes between pediatric CCVR patients who received EACA and TXA.
Our cohort was similar to other large pediatric craniosynostosis cohorts in terms of age, weight, gender, type of procedure, and ASA status, though we did have fewer patients with syndromic craniosynostosis compared to many of the published groups.3,5,14,17,23Intraoperative fluid management was in line with previously published studies.17,19,23 Transfusion rates in our cohort were lower than those previously reported in the literature, though similar to recent reports from single institutions. A large multicenter study (n=1,814) that included 33 institutions reported transfusion of RBC-containing products in nearly 90% of patients, FFP in over 20% of patients and platelets and cryoprecipitate in 2-3% of patients.5 Average RBC transfusion volume was 30 mL/kg. In our cohort, only 62% of patients received RBC transfusion, and transfusion volume was lower at 15 mL/kg. Other groups, however, have shown a more significant reduction in transfusion rates, such as Dadure et al. who showed a reduction in total transfusion from 70% in a placebo group to 37% in a group given TXA.17 Goobie et al. likewise showed a reduction in blood loss, transfusion volume, and even avoidance of all postoperative blood product transfusion in a pediatric CCVR cohort receiving TXA compared to placebo.23
We collected and analyzed intraoperative estimated blood loss and postoperative drain output volumes as measures of blood loss in our cohort. However, we know these measurements are highly variable and unreliable as indicators of true blood loss.24 We found that calculated blood loss in our cohort was higher than estimated blood loss and that blood loss continued into the postoperative period. All patients in our cohort received antifibrinolytic therapy, and there was no observed difference in calculated blood loss or estimated blood loss between the EACA and TXA groups. Post-operative drain output was statistically higher in the EACA group, but likely of no clinical significance for the volumes reported. Furthermore, not all patients had drains placed during surgery.
We looked carefully at postoperative complications with respect to possible side effects from antifibrinolytic therapy. While TXA and EACA are relatively safe and inexpensive medications, there is concern about the potential for thrombosis, increasing risk of seizures, and potential interference with the fibrinolysis necessary for wound healing.25 There were two thromboembolic events, but both related to arterial access devices (not venous thromboembolism) and both relatively minor in severity. Two patients did develop seizure activity post-operatively, one with concern with baseline increased potential based on underlying diagnosis. The other without clear etiology, but self-limited. One patient did have significant surgical site wound infection, but wound healing was not otherwise an issue in this cohort. A large meta-analysis of adult surgical trials using TXA did not show any increased risk for stroke, deep vein thrombosis, pulmonary embolism, myocardial infarction, or death. The adult data do show, however, that TXA is efficacious in decreasing blood transfusion.10,26–28 Without any evidence of a difference in outcomes between pediatric craniofacial surgery patients receiving EACA vs TXA, centers may consider other factors such as cost, drug availability, and safety.29,30 Aminocaproic acid is more cost-effective in most settings,29,31,32although there have been more issues with drug supply. There may be a slightly higher risk of seizures with TXA33, but there is not yet robust pediatric data to support this finding from retrospective review of adult surgical patients. Our center’s current practice is to use tranexamic acid, based primarily on drug availability. However, as we accumulate more data about the use of antifibrinolytic agents in children undergoing surgery, it will be important to keep cost, efficacy, and safety considerations in mind.
In this study, we tried to identify laboratory parameters associated with blood loss and transfusion to obtain a better understanding of the mechanisms of surgical coagulopathy in this population. Intraoperative laboratory values did predict perioperative calculated blood loss. A lower intraoperative platelet count and fibrinogen predicted decrease intraoperative CBL. Lower intraoperative platelet count also predicted decreased CBL. However, it is important to note that none of these patients were thrombocytopenic nor hypofibrinogenemic. In contrast, a higher intraoperative prothrombin time was associated with increased intraoperative CBL and a higher postoperative partial thromboplastin time was associated with increased postoperative CBL, possibly reflecting procoagulant protein losses or a more abnormal coagulation state. While there were no differences in laboratory parameters between the two antifibrinolytic groups, there were some interesting postoperative laboratory trends that suggest ongoing disturbance of the hemostatic system beyond the operative period. Our data set was insufficient to draw firm conclusions about coagulopathy in this period but suggests that future prospective laboratory-based studies looking at coagulation assays may help elucidate some of the mechanisms of this surgical induced coagulopathy. In a retrospective study, we were limited to analysis of laboratory markers collected by the clinical team, but it would be interesting to consider additional markers of coagulation and fibrinolysis, including D-dimer, plasminogen activity, and plasmin-antiplasmin complexes. Better understanding the mechanisms of coagulopathy in craniofacial surgery and making optimal use of antifibrinolytic therapy has the potential to improve bleeding and surgical outcomes for children with craniosynostosis. A prospective trial comparing EACA and TXA and analyzing perioperative hematologic parameters would be beneficial in confirming the findings in our study.