Neurodevelopmental impairment due to delayed brain development and brain injury is a fundamental problem in children with critical congenital heart disease (CCHD). Significant longterm motor-, cognitive-, and behavioral problems are the result of early postnatally and perioperatively induced brain injury. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of toxic free oxygen radicals, thereby limiting hypoxia-reperfusion damage. Both animal and neonatal studies suggest that administration of allopurinol reduces hypoxic-ischemic brain injury, is cardioprotective, and safe. This study aims to evaluate the efficacy and safety of allopurinol administered early postnatally and perioperatively in children with a CCHD requiring cardiac surgery with cardiopulmonary bypass.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
236
Allopurinol powder for solution for infusion (PFI) 20 mg/kg body weight per administration will be administered early postnatally (within 45 minutes and 12 hours after the first dose), preoperatively (12 hours before surgery), intraoperatively (during surgery) and postoperatively (24 hours after surgery) to the neonate in case of a prenatal CCHD diagnosis. Allopurinol PFI will be administered only pre-, intra- and postoperatively to the neonate in case of a postnatal CCHD diagnosis.
Mannitol powder for solution (PFI) placebo will be administered early postnatally (within 45 minutes and 12 hours after birth), preoperatively (12 hours before surgery), intraoperatively (during surgery), and postoperatively (24 hours after surgery) to the neonate in case of a prenatal CCHD diagnosis. Mannitol PFI-placebo will be administered only pre-, intra- and postoperatively to the neonate in case of a postnatal CCHD diagnosis.
University Medical Center Groningen (UMCG)
Groningen, Netherlands
RECRUITINGRadboud University Medical Center Nijmegen (Radboudumc)
Nijmegen, Netherlands
ACTIVE_NOT_RECRUITINGErasmus Medical Center Rotterdam (Erasmus MC)
Rotterdam, Netherlands
RECRUITINGUniversity Medical Center Utrecht (UMC Utrecht)
Utrecht, Netherlands
RECRUITINGRelevant parenchymatous brain injury on postoperative MRI
The presence or absence of relevant (moderate/severe) parenchymatous (ischemic or hemorrhagic) brain injury on postoperative MRI will be assessed, using the T1/T2/DWI and SWI weighted images.
Time frame: between birth and 1 month after cardiac surgery
Rate of children that are considered 'too unstable for postoperative MRI'
This decision is based on the circulatory and respiratory status of the child before the planned postoperative MRI, as included in local guidelines (not part of this protocol) of each participating center.
Time frame: between birth and 1 month after cardiac surgery
Incidence of mortality
Defined as death until one month postoperatively.
Time frame: between birth and 1 month after cardiac surgery
Brain injury severity score on pre- and postoperative MRI
An MRI score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum \[Weeke L, et al. J Pediatr 2018\]. The score will be compared between groups (allopurinol vs placebo).
Time frame: between birth and 1 month after cardiac surgery
Volume of hypoxic-ischemic brain injury on pre- and postoperative MRI
To assess whether there are differences between groups (allopurinol vs placebo) in volume (mm3) of hypoxic-ischemic brain lesions using a fully automatic method for detection and quantification of ischemic lesions in diffusion-weighted MR images \[Murphy K, et al. Neuroimage Clin 2017\].
Time frame: between birth and 1 month after cardiac surgery
Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively
Time frame: between birth and 1 month after cardiac surgery
Ventricular ejection fraction (%) pre- and postoperatively
Time frame: between birth and 1 month after cardiac surgery
Brain function: Seizure activity on aEEG (presence or absence) postnatally and postoperatively
Time frame: 24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery
Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively
Time frame: 24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery
General movements and motor optimality score
Video recordings will be analyzed following the global general movement categories (normal, poor repertoire, cramped-synchronized, or chaotic) and the motor optimality score \[Einspieler C, et al. Dev Med Child Neurol. 2016\]. A higher score expresses a more optimal performance. Scores will be compared between groups (allopurinol vs placebo).
Time frame: at 3 months
Neurodevelopment
To assess motor, cognitive, speech and language development using the Bayley Scales of Infant and Toddler Development - Third Edition - NL (Bayley-III-NL). An average Bayley-III-NL score is 100, one standard deviation (SD) above or below the mean concerns 15 points. Scores will be compared between groups (allopurinol vs placebo).
Time frame: at 24 months
Quality of Life (scores and subscores): TNO-AZL TAPQoL
The TNO-AZL Questionnaire for Preschool Children's Health-Related Quality of Life (TAPQoL) will be assessed to give insight in the quality of life of both children with CCHD and their parents. A higher score indicates a better quality of life. Scores will be compared between groups (allopurinol vs placebo).
Time frame: at 24 months
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