Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

Congenital Heart Disease Clinical Trial

Official title:

Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00513240
• Other study ID #: R21HD5550101
• Secondary ID: IND #10001109421
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 2006
• Est. completion date: September 2015

Study information

• Verified date: January 2020
• Source: Baylor College of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: September 2015
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Days

Eligibility

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).

Related Conditions & MeSH terms

• Aortic Arch Hypoplasia or Interruption
• Congenital Heart Disease
• Heart Diseases
• Hypoplastic Left Heart Syndrome
• Transposition of Great Vessels
• Transposition of the Great Arteries

Intervention

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
• 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. .

Locations

Country	Name	City	State
United States	Texas Children's Hospital	Houston	Texas

Sponsors (3)

Lead Sponsor	Collaborator
Baylor College of Medicine	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), The Dana Foundation

Country where clinical trial is conducted

United States, 

References & Publications (19)

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 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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]. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005 Jan 5;293(1):90-5. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relative Difference in Total Maturity Score (TMS) From Preoperative Brain MRI to 7 Day Postoperative MRI	TMS is a measure of developmental maturity of the brain as assessed from T1 and T2-weighted images, grading myelination, cortical infolding, involution of the germinal matrix, and presence of bands of migrating glial cells. The brain MRIs were reviewed for infarction, hemorrhage, white matter injury (WMI), or dural sinovenous thrombosis (DVST). Injuries in each category are scored 0 for none, 1 for mild, 2 for moderate, 3 for severe. The score in each category is then multiplied by a proposed outcome significance multiplier. A total injury score of 0 signifies no injury, 1-5 a mild injury, 6-10 a moderate injury, and >10 a severe injury. Range of scores is 0 - 51. Lower scores indicate less injury.; The results present the relative difference of this score between the pre- and post-operative MRI. This was calculated as ((Post-operative MRI TMS - Pre-operative MRI TMS) / (Absolute(Pre-operative MRI TMS)) ). The proportion is then converted into a percentage.	7 days postoperatively.
Primary	Scores on Bayley Scales of Infant Development III at Age 1 Years.	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.	1 year postoperatively
Secondary	EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures).		72 hours postoperatively.
Secondary	Pharmacokinetics of High Dose Erythropoetin: 7 Erythropoetin Levels in First 24 Hours After First Dose (Maximum EPO Plasma Concentration)		24 hours after first EPO dose.

External Links

•   American Heart Association Web Page--Congenital Heart Disease
•   Baylor College of Medicine Web Site
•   Congenital Cardiac Anesthesia Society Web Page
•   National Institutes of Health: National Institute of Child Health and Developement Web Site
•   Texas Children's Hospital Web Site