The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery

Introduction: Over 90% of open craniosynostosis surgical procedures are associated with a
transfusion of blood or blood products. Goobie et. al. recently showed that tranexamic acid
in a dose of 50 mg/kg/15min and 5 mg/kg/h significantly reduced blood loss and transfusion
requirements as well as the overall exposure of children to donor PRBC by two thirds.
However, using a moderately high dosing regimen, TXA plasma concentrations were shown to far
exceed the accepted therapeutic level (by over 10 fold). No side effects of TXA were found in
this study but a recent study suggests that currently recommended high to moderate TXA dosing
regimens are potentially associated with neurological complications in children. Goobie et.
al. developed a population pharmacokinetic model of TXA and simulated a dose response curve
for this population. From this model and simulation, it appears that reducing the loading
dose to 10 mg/kg/15 min followed by a 5 mg/kg/h infusion is adequate to maintain plasma
concentrations above the accepted therapeutic level of 20ug/mL.

It is important to test and validate this reduced dosage scheme in a multicenter study. The
hypothesis is that this reduced dosage scheme (10 mg/kg loading dose and 5 ug/kg/h) is as
effective as the higher dosage scheme (50 mg/kg loading dose and 5 mg/kg/h) in decreasing
blood loss and transfusion requirements in children undergoing open craniosynostosis surgery.
Thus the PK/PD profile of TXA in craniosynostosis patients will be determined with genomics
explored as a cause of interpatient variability in the response to tranexamic acid.

Experimental Design: With IRB approval and informed consent 68 pediatric patients aged 3 m to
6 years coming for open craniofacial surgery will be randomized in a prospective double blind
fashion to either the current standard intravenous TXA dose (50mg/kg/15min and 5 mg/kg/h) or
this lower TXA dose (10 mg/kg/15min and 5 mg/kg/h) until the end of surgery. A standardized
anesthetic and well defined fluid, blood and blood product management protocols will be
followed with improved modifications from the previously described protocol.

Data Analysis Plan: A preliminary power analysis indicated that a total sample size of 56
children (28 in randomized each group) would provide 80% statistical power to test whether
the difference in average blood loss is equivalent to within 25% (ie 15 cc/kg) assuming a
standard deviation of 30% ie +/- 22 ml/kg (moderate effect size = 0.68) . We plan to
randomize 68 patients; 34 per group to ensure that we meet our sample size requirements while
accounting for a potential 20% patient drop out.

Specific Aims:

1. Determine the efficacy of TXA (PD) in infants and children undergoing open craniofacial
surgery with this lower dosage scheme.

2. Determine the population pharmacokinetics (PK) of TXA in infants and children undergoing
open craniofacial surgery with this dosage scheme.

3. Determine the influence of genetics on response to TXA.

4. Attempt to better define efficacy of TXA in a direct manner using a novel and innovative
approach by obtaining pre and post biological markers of fibrinolysis (as bleeding and
blood loss are difficult to measure accurately and are an indirect measure of TXA
efficacy of inhibition of fibrinolysis.

Inclusion Criteria:

- Patients (age range 3 months to 6 years) undergoing craniosynostosis repair,
fronto-orbital advancement surgery and cranial remodeling surgery (i.e. total cavernal
remodeling surgery).

Exclusion Criteria:

- Preexisting hematological abnormality (defined as a positive history of bleeding
disorder or a known diagnosis of a genetic or acquired bleeding disorder)

- Preexisting coagulation defect (defined as PT, PTT or INR >1.5 times normal or a n
pre-existing genetic or acquired coagulation defect))

- Preexisting hepatic, renal, vascular, ocular and/or metabolic disorder

- History of acetylsalicylate ingestion within the last 14 days.

- History of NSAIDs ingestion with 2 days of the scheduled surgery date