Preventing brain injury in newborns with congenital heart disease: brain imaging and innovative trial designs.
OBJECTIVE
Newborns with congenital heart disease are at high risk for brain injury and adverse neurodevelopmental outcomes. MRI enables the objective determination of the severity of brain injury in critically ill newborns with congenital heart disease. We will rationalize the use of MRI as a surrogate for neurodevelopmental outcome and describe novel randomization techniques that can be used in trials in this population.


METHODS
This article describes the evidence for the use of MRI and the link with neurodevelopmental outcome established in newborns. We also discuss the use of adaptive randomization techniques for future clinical trials in newborns with congenital heart disease. These strategies will be highlighted using an example.


RESULTS
Brain injuries occur with high frequency in newborns with congenital heart disease. It is not until school age that the full extent of neurological sequelae becomes apparent and the rapid pace of innovation in neonatal cardiac surgery prevents timely evaluation of changes in care. MRI provides a timely, safe, and reliable outcome measure and has been extensively studied in newborns with other conditions in which the link between brain injury and neurodevelopmental outcome has been established. Clinical trials using MRI as an outcome measure as well as adaptive randomization can improve the efficiency of such trials.


CONCLUSIONS
Clinical trials of brain protection are urgently needed in newborns with congenital heart disease given the unacceptable frequency of brain injury in this population; MRI provides an early surrogate marker of long-term neurodevelopmental outcome and adaptive randomization can be used to improve the efficiency of these clinical trials.
Sherlock
Rebecca L
RL
Division of Neonatology, Children's and Women's Health Center of British Columbia, 1R46, 4480 Oak Street, Vancouver, British Columbia, V6H 3V1, Canada. rsherlock@cw.bc.ca
McQuillen
Patrick S
PS
Miller
Steven P
SP
D015415:Biomarkers / Q000032:analysis; D002658:Developmental Disabilities / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D042241:Early Diagnosis; D006330:Heart Defects, Congenital / Q000150:complications*; D006801:Humans; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000175:diagnosis* / Q000209:etiology / Q000517:prevention & control*; D008279:Magnetic Resonance Imaging / Q000379:methods / Q000592:standards*; D017063:Outcome Assessment, Health Care; D011237:Predictive Value of Tests; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic / Q000592:standards / Q000639:trends; D020521:Stroke / Q000175:diagnosis* / Q000209:etiology / Q000517:prevention & control*
D015415:Biomarkers