Erythropoetin Neuroprotection for Neonatal Cardiac Surgery

Phase 1

Completed

Conditions: Congenital Heart Disease
Transposition of the Great Arteries
Hypoplastic Left Heart Syndrome
Aortic Arch Hypoplasia or Interruption

Interventions: Drug: Erythropoetin
Drug: Normal saline

Registration Number: NCT00513240

Lead Sponsor: Baylor College of Medicine

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 62

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EPO group	Erythropoetin	Patients randomized to receive the 3 doses of erythropoetin.
Control group.	Normal saline	Patients randomized to receive 3 doses of normal saline control.

Primary Outcome Measures

Name	Time	Method
Relative Difference in Total Maturity Score (TMS) From Preoperative Brain MRI to 7 Day Postoperative MRI	7 days postoperatively.	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.
Scores on Bayley Scales of Infant Development III at Age 1 Years.	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

Name	Time	Method
EEG Seizure Burden in the First 72 Postoperative Hours. (Total Minutes of EEG Seizures).	72 hours postoperatively.
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.