Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

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Brief Title

Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

Official Title

Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

Brief 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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Relative Difference in Total Maturity Score (TMS) From Preoperative Brain MRI to 7 Day Postoperative MRI

Secondary Outcome

 EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures).

Condition

Congenital Heart Disease

Intervention

Erythropoetin

Study Arms / Comparison Groups

 EPO group
Description:  Patients randomized to receive the 3 doses of erythropoetin.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

62

Start Date

September 2006

Completion Date

September 2015

Primary Completion Date

September 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Neonates (<30 days) undergoing cardiac surgery with cardiopulmonary bypass will be
             enrolled.

          -  Inclusion criteria include patients with:

               -  single ventricle: hypoplastic left heart syndrome or variant undergoing Norwood
                  Stage I or Sano palliation (SV group);

               -  patients with D-transposition of the great vessels with or without ventricular
                  septal defect (VSD) undergoing arterial switch operation with VSD closure if
                  needed (ASO group); and

               -  patients with interrupted or hypoplastic aortic arch with intracardiac defects
                  (VSD, ASD, or subaortic stenosis) who are undergoing complete 2- ventricle repair
                  including aortic arch advancement(AAA group), any other 2 ventricle lesion
                  scheduled for complex anatomic repair.

        Exclusion Criteria:

          -  Gestational age less than 35 weeks at birth

          -  Weight less than 2 kg

          -  Known recognizable dysmorphic syndrome

          -  Surgery not requiring cardiopulmonary bypass

          -  Preoperative cardiac arrest requiring chest compressions for greater than 3 minutes

          -  Inability to enroll the patient greater than 12 hours preoperatively

          -  Aortic crossclamping is not used

          -  CPB times are anticipated to be less than 60 minutes

          -  A nadir temperature on bypass greater than 25° C is planned.

          -  Presence of known contraindications to EPO administration-sustained systolic blood
             pressure >100, hemoglobin .18 g/dL, known allergy to EPO or one of its components

          -  Platelet count >600,000 per dL, INR <0.8.

          -  Maternal history of major vascular thrombosis, or multiple fetal loss (3 or more
             spontaneous abortions).
      

Gender

All

Ages

N/A - 30 Days

Accepts Healthy Volunteers

No

Contacts

Dean B. Andropoulos, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00513240

Organization ID

R21HD5550101

Secondary IDs

IND #100011

Responsible Party

Principal Investigator

Study Sponsor

Baylor College of Medicine

Collaborators

 The Dana Foundation

Study Sponsor

Dean B. Andropoulos, M.D., Principal Investigator, Baylor College of Medicine/Texas Children's Hospital


Verification Date

January 2020