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Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

This study is ongoing, but not recruiting participants.
ClinicalTrials.gov Identifier:
First Posted: August 8, 2007
Last Update Posted: January 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The Dana Foundation
Texas Children's Hospital
Information provided by (Responsible Party):
Dean Andropoulos, Baylor College of Medicine
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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

Resource links provided by NLM:

Further study details as provided by Dean Andropoulos, Baylor College of Medicine:

Primary Outcome Measures:
  • 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.

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

Enrollment: 62
Study Start Date: September 2006
Estimated Study Completion Date: January 2017
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.


Information from the National Library of Medicine

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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:
Andropoulos DB, Brady K, Easley RB, Dickerson HA, Voigt RG, Shekerdemian LS, Meador MR, Eisenman CA, Hunter JV, Turcich M, Rivera C, McKenzie ED, Heinle JS, Fraser CD Jr. Erythropoietin neuroprotection in neonatal cardiac surgery: a phase I/II safety and efficacy trial. J Thorac Cardiovasc Surg. 2013 Jul;146(1):124-31. doi: 10.1016/j.jtcvs.2012.09.046. Epub 2012 Oct 23.
Kellert BA, McPherson RJ, Juul SE. A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats. Pediatr Res. 2007 Apr;61(4):451-5.
McPherson RJ, Demers EJ, Juul SE. Safety of high-dose recombinant erythropoietin in a neonatal rat model. Neonatology. 2007;91(1):36-43. Epub 2006 Nov 10.
Galli KK, Zimmerman RA, Jarvik GP, Wernovsky G, Kuypers MK, Clancy RR, Montenegro LM, Mahle WT, Newman MF, Saunders AM, Nicolson SC, Spray TL, Gaynor JW. Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg. 2004 Mar;127(3):692-704. Erratum in: J Thorac Cardiovasc Surg. 2004 Sep;128(3):498. Galli, Kristen K [corrected to Galli, Kristin K].
Andropoulos DB, Stayer SA, Diaz LK, Ramamoorthy C. Neurological monitoring for congenital heart surgery. Anesth Analg. 2004 Nov;99(5):1365-75; table of contents. Review.
Andropoulos DB, Stayer SA, McKenzie ED, Fraser CD Jr. Regional low-flow perfusion provides comparable blood flow and oxygenation to both cerebral hemispheres during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg. 2003 Dec;126(6):1712-7.
Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005 Jan 5;293(1):90-5. Review.
McQuillen PS, Barkovich AJ, Hamrick SE, Perez M, Ward P, Glidden DV, Azakie A, Karl T, Miller SP. Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke. 2007 Feb;38(2 Suppl):736-41.
Chang YS, Mu D, Wendland M, Sheldon RA, Vexler ZS, McQuillen PS, Ferriero DM. Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res. 2005 Jul;58(1):106-11. Epub 2005 May 5.
Ballweg JA, Wernovsky G, Gaynor JW. Neurodevelopmental outcomes following congenital heart surgery. Pediatr Cardiol. 2007 Mar-Apr;28(2):126-33. Epub 2007 Jan 29. Review.
Karl TR, Hall S, Ford G, Kelly EA, Brizard CP, Mee RB, Weintraub RG, Cochrane AD, Glidden D. Arterial switch with full-flow cardiopulmonary bypass and limited circulatory arrest: neurodevelopmental outcome. J Thorac Cardiovasc Surg. 2004 Jan;127(1):213-22.
Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G, Lin M, Bellinger DC. The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg. 2003 Nov;126(5):1397-403.
Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G, Blomgren K, Wang X. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009 Aug;124(2):e218-26. doi: 10.1542/peds.2008-3553. Epub 2009 Jul 27.
Andropoulos DB, Mizrahi EM, Hrachovy RA, Stayer SA, Stark AR, Heinle JS, McKenzie ED, Dickerson HA, Meador MR, Fraser CD Jr. Electroencephalographic seizures after neonatal cardiac surgery with high-flow cardiopulmonary bypass. Anesth Analg. 2010 Jun 1;110(6):1680-5. doi: 10.1213/ANE.0b013e3181dd5a58. Epub 2010 Apr 30.
Andropoulos DB, Hunter JV, Nelson DP, Stayer SA, Stark AR, McKenzie ED, Heinle JS, Graves DE, Fraser CD Jr. Brain immaturity is associated with brain injury before and after neonatal cardiac surgery with high-flow bypass and cerebral oxygenation monitoring. J Thorac Cardiovasc Surg. 2010 Mar;139(3):543-56. doi: 10.1016/j.jtcvs.2009.08.022. Epub 2009 Nov 11.
McPherson RJ, Juul SE. Erythropoietin for infants with hypoxic-ischemic encephalopathy. Curr Opin Pediatr. 2010 Apr;22(2):139-45. doi: 10.1097/MOP.0b013e328336eb57. Review.
Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA, Mayock DE. A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety. Pediatrics. 2008 Aug;122(2):383-91. doi: 10.1542/peds.2007-2711.
Fauchère JC, Dame C, Vonthein R, Koller B, Arri S, Wolf M, Bucher HU. An approach to using recombinant erythropoietin for neuroprotection in very preterm infants. Pediatrics. 2008 Aug;122(2):375-82. doi: 10.1542/peds.2007-2591.
Brown MS, Eichorst D, Lala-Black B, Gonzalez R. Higher cumulative doses of erythropoietin and developmental outcomes in preterm infants. Pediatrics. 2009 Oct;124(4):e681-7. doi: 10.1542/peds.2008-2701. Epub 2009 Sep 28.

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 Submitted: August 7, 2007
First Posted: August 8, 2007
Results First Submitted: January 24, 2014
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

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