A Prospective, Randomized, Placebo-Controlled High-Dose Erythropoetin Neuroprotection Trial for Newborns Undergoing Cardiac Surgery with Cardiopulmmonary Bypass

Dean B. Andropoulos, M.D.

Baylor College of Medicine

Funded in December, 2006: $100000 for 3 years
LAY SUMMARY . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Using MRI to Assess Whether EPO Protects Infants’ Brains after Bypass Surgery

Foundation funds will support the MRI imaging component of an ongoing controlled clinical study to see if high-dose erythropoietin (EPO) protects against brain injury in infants with congenital heart disease who undergo cardiac bypass surgery.  The other parts of the study are being supported from funds from the National Institutes of Health (NIH) and internal institutional funds.

Congenital heart disease occurs in nearly one of every 100 live births, and about 25 percent of these infants require cardiac bypass surgery.  Although improvements have cut the surgical death rate to about five percent, up to 69 percent of such infants can incur long-term neurodevelomental impairments.  The Baylor researchers have found a high incidence of hypoxia (reduced oxygen flow) in surgery patients. Hypoxia most likely stems from the need to use deep hypothermic circulatory arrest for the procedure.  EPO is an approved biologic.  It increases production of red blood cells that carry oxygen to the body’s tissues, including the brain.  Studies suggest that EPO’s increase in blood oxygen may prevent brain hypoxia and its damage to brain white matter, the neuronal communication cables, during cardiac bypass surgery.  Evidence for this comes from experimental animal and primate studies, in which EPO was found to reduce neuronal death by 50-70 percent, whether administered before, during or even a few hours after hypoxia.

Baylor researchers have received NIH and internal institution funds to undertake a randomized controlled trial of EPO in infants undergoing cardiac bypass surgery and will assess surgical hypoxia outcomes.  With Dana support, the researchers will use MRI imaging in these study participants to determine whether the therapy reduces brain injury from the surgery, and improves short and longer-term neurodevelopmental outcomes.  Infants will be randomized to receive either EPO or a placebo the day before, the day of, and the day after surgery. MRI imaging will be undertaken immediately prior to surgery, and at seven days and three to six months following surgery.  Neurodevelopment tests of the infants will be made one, three, and five years after surgery.  Testing of participants in these later years will occur beyond the period of Dana funding. Through the MRI findings and neurodevelopmental tests, the study will reveal whether EPO has a neuroprotective effect.

Significance:  If imaging and neurodevelopmental testing demonstrates that EPO has a neuroprotective effective against white matter damage from hypoxia in infants undergoing surgery for congenital heart disease, the findings would profoundly influence surgical practice to improve neurodevelopmental outcomes.

HYPOTHESIS

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Hypothesis:
Our hypothesis is that high dose EPO will have neuroprotective effects in neonatal cardiac surgery, reducing both early and late neurological and neurodevelopmental injury. Early primary outcome improvement is defined by reduction in postoperative MRI severity of injury score by 25%. Late outcome improvement is defined by increase in Bayley Scales of Infant Development score by 18% at age 3 years.

Goals:
1. To determine the effect of high-dose perioperative EPO on short and long term neurological outcomes in neonates undergoing cardiac surgery with an optimized cardiopulmonary bypass strategy, using MRI as primary early outcome modality.
2.  To determine EPO tolerability and safety with short term high dose administration. 
3. To determine EPO pharmacokinetics in this population.
4. To determine the relationship of neurological monitoring, specifically near-infrared spectrscopy (NIRS), to neurological outcomes with an optimized cardiopulmonary bypass technique in neonates that avoides deep hypothermic circulatory arrest, and to determine if EPO affects this relationship

Methods:
We will randomize newborns scheduled for cardiac surgery for the arterial switch operation, Norwood Stage I palliation, or aortic arch reconstruction.  Each patient will undergo NIRS monitoring pre-, intra-, and postoperatively for a total of 96 hours; pre- and postoperative EEG monitoring during the same period; and a brain MRI immediately prior to surgery, and 7 days after surgery.  Patients will be randomized to receive EPO, 1000 units/kg per dose IV, or placebo, administered 12-24 hours before surgery, the day of surgery, and the day after surgery.  Patients will also have a third brain MRI at 3-6 months; and a complete neurodevelopmental assessment at age 1, 3, and 5 years. The early primary outcome variable will be MRI severity of injury score; and the later primary outcome will be Bayley Scales of Infant Development scores.  MRI parameters include T1 and T2 weighted imaging, diffusion tensor imaging, volumetrics, MR spectroscopy, and severity of hypoxic ischemic injury score for infarction, hemorrhage, periventicular leukomalacia, thrombosis, and other injuries. Early MRI findings will be correlated with later MRI changes, and with long term neurodevelopmental outcomes.

SELECTED PUBLICATIONS

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Andropoulos D.B., Stayer S.A., McKenzie E.D., and Fraser C.D.  Regional low-flow cerebral 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.

Andropoulos D.B., Stayer S.A., Diaz L.K., and Ramamoorthy C.  Neurologic monitoring for congenital heart surgery.  Anesth Analg. 2004 Nov;99(5):1365-75; table of contents.