Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
Condition: Congenital Heart Disease; Hypoplastic Left Heart Syndrome; Transposition of the Great Arteries; Aortic Arch Hypoplasia or Interruption
MeSH terms: Heart Diseases; Heart Defects, Congenital; Hypoplastic Left Heart Syndrome; Transposition of Great Vessels
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Brain problems occur in neonatal open heart surgery with a frequency of 20-70%, seen on
      neurological examination, brain imaging such as magnetic resonance imaging (MRI), or long
      term development problems such as learning disorders and hyperactivity syndromes. This study
      aims to determine if erythropoetin, a natural hormone made in the body, protects the brain
      from damage when given in high doses before and during neonatal open heart surgery. We will
      use brain MRI, brain wave tests (EEG), neurological examination, and long term developmental
      outcome testing to see if erythropoetin is better than salt water injection (placebo) in
      protecting the brain.
    

Detailed description: 
      Hypothesis: Erythropoetin (EPO) will protect the neonatal brain in the perioperative period
      for congenital heart surgery.

      Using a prospective, randomized, placebo-controlled, double-blinded design, the specific aims
      of this study are:

        1. To determine the effect of perioperative EPO on short and long term neurological
           outcomes in neonates undergoing cardiac surgery with an optimized cardiopulmonary bypass
           strategy.

        2. To determine EPO tolerability and safety with short term administration.

        3. To determine EPO pharmacokinetics in this population.

        4. To determine the relationship of neurological monitoring, specifically NIRS, to
           neurological outcomes with an optimized cardiopulmonary bypass technique in neonates
           that avoids deep hypothermic circulatory arrest, and to determine if EPO affects this
           relationship.

      Protocol: Neonates undergoing arterial switch, Norwood, or aortic arch advancement/other
      complete 2 ventricle repair, >35 weeks gestation and ≥2.0 kg are eligible.

      Preop day 1:NIRS for 12-24 hours, neuro exam, and Study drug dose #1: EPO 500 units/kg or
      saline placebo 12-72 hours before surgery. EPO Pharmacokinetic data for 25-50 consenting
      patients.

      Day of surgery: Brain MRI immediately preop. Anesthesia/CPB per our standard practice
      (fentanyl 100-200 mcg/kg, midazolam, isoflurane, epsilon-aminocaproic acid, 75 mg/kg IV load
      to patient and CPB prime, and 75 mg/kg/hr infusion in OR) with ACP guided by TCD, pH stat,
      hct 30-35, avoid DHCA.

      POD #1: Study drug dose #2: EPO 500 units/kg or saline placebo 24 hours after dose #2.

      For 72 hours postop, NIRS monitoring. All monitor data collected electronically.

      POD #3: Study drug dose #3: EPO 500 units/kg or saline placebo 48 hours after dose #3.

      7 days postop: Brain MRI. (pentobarbital IV). Neuro exam before discharge. 3-6 months: Brain
      MRI immediately before or after 2nd surgery, or as outpatient (IV pentobarb or
      propofol/midazolam-may use N2O/sevo for induction, cannot intubate if outpatient; OR if
      cardiac MRI at same time, any indicated anesthetic technique). NIRS x 24h after 2nd surgery.

      1,and 3 years: Bayley Scales of Infant Development III. 5 years: Battery of
      neurodevelopmental tests.

      Early primary outcome variable: MRI severity of injury score (decrease by 25%). Late outcome
      variable Bayley Scales of Infant Development score: improvement by 18% at age 1 years.

      Sample size: 60 patients: stratified into 3 groups to give power 0.85, alpha 0.05. Expect to
      accrue 2-4 patients per month.
    

Intervention name(s): Erythropoetin; Normal saline
Intervention type(s): Drug; Drug
Intervention description(s): Erythropoetin 500 units/kg IV x 3 : dose 1. 12-72 hours preoperatively, dose 2. Postoperative day #1, 48 hours after separating from cardiopulmonary bypass, and dose 3. postoperative day #3, 48 hours after dose #2; Normal saline placebo in 3 doses:dose 1. 12-72 hours preoperatively, dose 2. Postoperative day #1, 48 hours after separating from cardiopulmonary bypass, and dose 3. postoperative day #3, 48 hours after dose #2.
.
Other intervention name(s): Procrit; Epoetin alpha; Saline placebo
Intervention MeSH terms: Epoetin Alfa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: erythropoetin; neuroprotection; neonate; cardiac; magnetic resonance imaging; brain magnetic resonance imaging; electroencephalogram