Cerebrum and Cardiac Protection With Allopurinol in Neonates With Critical Congenital Heart Disease Requiring Cardiac Surgery With Cardiopulmonary Bypass

Study Overview
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Brief Summary
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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.

Official Title
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Cerebrum and Cardiac Protection With Allopurinol in Neonates With Critical Congenital Heart Disease Requiring Cardiac Surgery With Cardiopulmonary Bypass

Conditions
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Congenital Heart Disease in Children, Neuroprotection

Intervention / Treatment
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* Drug: Allopurinol
* Drug: Mannitol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. Patient considered moribund. Decision for comfort care only.

Ages Eligible for Study
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Maximum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Allopurinol<br> | Drug: Allopurinol<br>* 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.<br>|
| Placebo Comparator: Placebo<br> | Drug: Mannitol<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | between birth and 1 month after cardiac surgery | 
| Incidence of mortality | Defined as death until one month postoperatively. | between birth and 1 month after cardiac surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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]. | between birth and 1 month after cardiac surgery | 
| Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively |  | between birth and 1 month after cardiac surgery | 
| Ventricular ejection fraction (%) pre- and postoperatively |  | between birth and 1 month after cardiac surgery | 
| Brain function: Seizure activity on aEEG (presence or absence) postnatally and postoperatively |  | 24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery | 
| Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively |  | 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). | 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). | at 24 months | 
| Executive functioning in comparison to healthy controls | Both 'hot' executive functions (snack and gift delay tasks) and 'cool' executive functions (six boxes, memory for location, and visual search task) will be tested and scored. A higher score indicates a better performance. The results of the executive function tasks will be compared with healthy children from the PreCool study [Veen A, Veen I van der, Heurter AMH, et al. Pre-Cool cohortonderzoek, technisch rapport tweejarigen cohort. Amsterdam: Kohnstamm Instituut Rapport 877, Projectnummer 20379]. A higher score reflects a more optimal perfomance. Scores will be compared between groups (allopurinol vs placebo). | 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). | at 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital Heart Disease, Neuroprotection, Allopurinol, Brain injury, Cardiopulmonary bypass, Brain function, Brain oxygenation, Cardiac function, Neurodevelopmental outcome, Cardiac surgery, Hypoxic-ischemic brain injury, Neonates