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.