Does Tranexamic Acid Decrease Blood Loss in Pediatric Idiopathic Scoliosis Surgery?
Condition: Adolescent Idiopathic Scoliosis
MeSH terms: Scoliosis; Hemorrhage
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Adolescent idiopathic scoliosis surgery is an extensive procedure associated with significant
      blood loss frequently requiring the transfusion of blood. Tranexamic acid (TXA) is a
      synthetic antifibrinolytic (prevents breakdown of the blood clot) that has been used to
      extensively reduce transfusion in pediatric major surgery, including cardiac, craniofacial
      and orthopedic surgery. In this prospective randomized double-blinded study, the
      investigators wish to evaluate the hypothesis that TXA is more effective than standard of
      care at decreasing blood loss and blood transfusion perioperatively in children and
      adolescents undergoing idiopathic scoliosis surgery.
    

Detailed description: 
      This prospective randomized double-blinded study will enroll 120 children and adolescents
      ages undergoing scoliosis repair with the diagnosis of idiopathic scoliosis. The primary aim
      is to determine if intravenous infusion of TXA is more effective than standard care (no TXA)
      at decreasing blood loss and blood transfusion perioperatively in children and adolescents
      presenting for scoliosis surgery.

      Aims:

        1. Investigate and compare the efficacy of TXA (as measured by intraoperative blood loss
           and blood transfusion) intravenously administered during surgery vs placebo in patients
           with idiopathic scoliosis coming for surgery.

        2. Determine the PK profile of TXA in children and adolescents undergoing scoliosis
           surgery.

        3. Investigate the contribution of these different factors (plasma concentration of TXA,
           age related differences in PK/PD and renal function, and polymorphism of the Plasminogen
           activator inhibitor-1 (PAI-1) gene and PAI-1 levels with TXA efficacy in pediatric
           patients undergoing and scoliosis surgery.

        4. Determine the safety profile of intravenous TXA in children and adolescents presenting
           for scoliosis surgery.

      Following a standardized general anesthetic protocol, patients coming with idiopathic
      scoliosis will be randomized to either:

        1. placebo i.e. saline 0.9% (intravenous injection)

        2. intravenous TXA given as a loading dose over 15 minutes of 50 mg/kg bolus ( 30- 60
           minutes prior to surgical incision) and 10 mg/kg/hr infusion for the duration of the
           surgery.

      During the surgery, we will follow standardized, defined fluid, blood and blood production
      management protocols.

      The following data are part of routine patient care and will be collected for study purposes:

        1. Age, weight, height, gender, race, coexisting diseases, preoperative hemoglobin,
           hematocrit, platelets, PT, PTT, and INR, creatinine.

        2. Intraoperative data: total volume of intraoperative blood loss as estimated by weighing
           sponges amount of blood in suction canisters, total volumes and units of blood products
           administered, total volume of cell saver blood administered, total volumes of
           crystalloid and colloid agents administered, hemodynamic parameters; mean arterial blood
           pressure & heart rate, total urine output, total surgical time, and number spinal levels
           involved.

        3. Laboratory data: Perioperative baseline and serial hemoglobin, hematocrit, platelet
           count, PT, PTT, INR and fibrinogen as dictated by standard clinical practice.

        4. Postoperative data collection will include: blood transfusion requirement in the first
           24 hours after surgery, amount of blood collected in the surgical drains for the first
           24 hours postoperatively, the occurrence of any postoperative complications and duration
           of ICU and hospital stay.

      A research team member will follow the patient daily after the surgery and a follow-up phone
      call will be made to the family at one month after discharge from the hospital with the aim
      to identify adverse events related to TXA. Potential adverse advents include hypersensitivity
      or allergic reaction to tranexamic acid, thromboembolic events, neurological complications,
      and development of renal insufficiency. Adverse events will be reported immediately to the
      IRB as per institutional protocols. As the estimate of blood loss is somewhat inaccurate,
      blood loss will also be calculated as previously described.

      The following measures are not part of routine patient care but are required by the study
      protocol:

      During the course of the operation, a total of four samples consisting of 2 ml each of blood
      will be drawn from the arterial catheter for DNA, PAI-1 protein level, and baseline TXA.
      After the study drug infusion is started, subsequent 2 ml samples will be drawn utilizing one
      of four different sampling schemes randomly assigned.

      TXA plasma concentrations will be measured as described with some modifications we have made
      in our laboratory18. The samples will be immediately anticoagulated with ethylene diamine
      tetraacetic acid (EDTA) and stored on ice. Plasma will be separated by centrifugation (1000g
      x10 min at 4oC) and stored at -70 oC pending analysis for TXA concentrations. TXA plasma
      concentrations will be measured using high performance liquid chromatography (HPLC) after
      ultrafiltration and derivatization18.

      Recruitment Methods:

      Potential eligibility for the study will be identified via the surgical schedule which will
      be screened daily by a designated member of the research team. A cover letter, brochure, and
      consent form will be mailed to the prospective patient's family prior to the scheduled
      pre-operative appointment. The study protocol will be reviewed with the patient/family and
      all queries will be addressed on the day of the visit to the preoperative clinic prior to the
      scheduled date of surgery. Informed consent will be obtained from the parents/legal guardians
      as per institutional IRB guidelines. The child's assent (when appropriate) will also be
      obtained at least 24 hours before the scheduled surgery when possible.

      Data Analysis Plan:

      A preliminary power analysis indicated that a total sample size of 120 children randomized
      equally to TXA vs. standard of care (no TXA) will provide 80% power (α = 0.05, β = 0.20) to
      detect a decrease from 30% to 10% of patients loosing a significant amount of blood (defined
      as >/= 25 ml/kg) using a chi-square test of independent binomial proportions assuming a
      standard deviation of 25% (effect size = 1.2) (version 7.0, nQuery Advisor, Statistical
      Solutions, Saugus, MA).

      Adverse Event Criteria and Reporting Procedures:

      Potential adverse events include hypersensitivity or allergic reaction to tranexamic acid or
      any component, thromboembolic events, neurologic events such as seizures, hypotension (with
      rapid IV administration). In awake patients, the following has been reported: nausea,
      diarrhea or vomiting. The patients will be assessed the next day by a member of the research
      team and interviewed for the occurrence of any of these adverse events. In the event of a
      serious adverse event, it will be reported to the IRB immediately and the study halted until
      a thorough investigation into the cause can be made.

      Data and Safety Monitoring Plan Data collection for this study will include the collection of
      any data pertaining to adverse events. Any adverse events will be promptly reported to the
      IRB and the members of the research team responsible for data and safety monitoring. Data and
      safety monitoring will be reviewed by the research team every 10 subjects recruited or
      earlier if a specific problem is identified
    

Intervention name(s): Tranexamic Acid; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Following a standardized general anesthetic protocol, patients coming with idiopathic scoliosis will be randomized to either:
placebo i.e. saline 0.9% (intravenous injection)
intravenous TXA given as a loading dose over 15 minutes of 50 mg/kg bolus ( within an hour prior to surgical incision) and 10 mg/kg/hr infusion for the duration of the surgery.; Following a standardized general anesthetic protocol, patients coming with idiopathic scoliosis will be randomized to:
Placebo ( 0.9% Normal saline) intravenously given as a 0.5 ml/kg loading dose over 15 minutes followed by a 0.1 ml/kg/hr continuous infusion throughout the surgery or
TXA as previously described.
Other intervention name(s): Cyklokapron, TXA, TA; 0.9% Normal saline
Intervention MeSH terms: Tranexamic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Tranexamic acid, Blood loss