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Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

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ClinicalTrials.gov Identifier: NCT00513240
Recruitment Status : Active, not recruiting
First Posted : August 8, 2007
Results First Posted : May 19, 2014
Last Update Posted : January 6, 2017
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment Phase
Congenital Heart Disease Hypoplastic Left Heart Syndrome Transposition of the Great Arteries Aortic Arch Hypoplasia or Interruption Drug: Erythropoetin Drug: Normal saline Phase 1 Phase 2

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 Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
Study Start Date : September 2006
Primary Completion Date : September 2012
Estimated Study Completion Date : January 2017

Arms and Interventions

Arm Intervention/treatment
Experimental: EPO group
Patients randomized to receive the 3 doses of erythropoetin.
Drug: Erythropoetin
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
Other Names:
  • Procrit
  • Epoetin alpha
Placebo Comparator: Control group.
Patients randomized to receive 3 doses of normal saline control.
Drug: Normal saline

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 Name: Saline placebo

Outcome Measures

Primary Outcome Measures :
  1. MRI Severity of Injury Score [ Time Frame: 7 days postoperatively. ]
    MRI severity of injury score change from preoperative brain MRI to 7 day postoperative MRI(decrease by 25%). Scoring of infarction, hemorrhage, white matter injury, cerebral venous sinus thrombosis, or increased lactate on MR spectroscopy.

  2. Scores on Bayley Scales of Infant Development III at Age 1 Years. [ Time Frame: 1 year postoperatively ]
    3 domains of the Bayley Scales of Infant Development III: Cognitive, Language and Motor Minimum score = 45, maximum score = 155; Population mean = 100, SD = 15; Higher scores are indicative of better outcomes Language scores are reflective of receptive communication and expressive communication subscales. Motor scores are reflective of fine motor and gross motor subscales.

Secondary Outcome Measures :
  1. EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures). [ Time Frame: 72 hours postoperatively. ]
  2. Pharmacokinetics of High Dose Erythropoetin: 7 Erythropoetin Levels in First 24 Hours After First Dose. [ Time Frame: 24 hours after first EPO dose. ]

Eligibility Criteria

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Ages Eligible for Study:   up to 30 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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).
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00513240

United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The Dana Foundation
Texas Children's Hospital
Principal Investigator: Dean B. Andropoulos, M.D. Baylor College of Medicine/Texas Children's Hospital
More Information

Additional Information:

Responsible Party: Dean Andropoulos, Professor, Chief of Pediatric Anesthesiology, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00513240     History of Changes
Other Study ID Numbers: R21HD5550101
FDA IND #100011
Baylor GCRC #0942
First Posted: August 8, 2007    Key Record Dates
Results First Posted: May 19, 2014
Last Update Posted: January 6, 2017
Last Verified: November 2016

Keywords provided by Dean Andropoulos, Baylor College of Medicine:
magnetic resonance imaging
brain magnetic resonance imaging

Additional relevant MeSH terms:
Heart Diseases
Hypoplastic Left Heart Syndrome
Transposition of Great Vessels
Cardiovascular Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Congenital Abnormalities
Epoetin Alfa