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.
Neonates with a prenatally or postnatally confirmed diagnosis of CCHD requiring (anticipated) cardiac surgery with CPB within the first 4 weeks of life.
Informed consent provided by both parents.
Inability to enroll the patient before the start of delivery in case of prenatal diagnosis, or 24 hours before surgery in case of postnatal diagnosis.
Doubt whether the aortic arch anomaly before birth requires cardiac surgery with CPB in the neonatal period.
Gestational age below 36 weeks and/or birth weight less than 2000 gram.
Surgery not requiring cardiopulmonary bypass.
Parallel
Allopurinol
DrugAllopurinol 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
DrugMannitol 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.
Relevant 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.
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.
Incidence of mortality
Defined as death until one month postoperatively.
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).
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 \[Murphy K, et al. Neuroimage Clin 2017\].
Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively
Ventricular ejection fraction (%) pre- and postoperatively
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dr. M.J.N.L. Benders
Lead sponsor
UMC Utrecht
Sponsor institution
ZonMw: The Netherlands Organisation for Health Research and Development
Collaborator
University Medical Center Groningen
Collaborator
Erasmus Medical Center
Collaborator
University Medical Center Nijmegen
Collaborator
ACE Pharmaceuticals BV
Collaborator
