CRUCIAL: Cerebrum and Cardiac Protection With Allopurinol in Neonates With Critical Congenital Heart Disease Requiring Cardiac Surgery With Cardiopulmonary Bypass
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Allopurinol
|
Drug: Allopurinol
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.
|
| Placebo Comparator: Placebo
|
Drug: Mannitol
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.
|
Outcome Measures
Primary Outcome Measures
- Relevant parenchymatous brain injury on postoperative MRI [between birth and 1 month after cardiac surgery]
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' [between birth and 1 month after cardiac surgery]
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 [between birth and 1 month after cardiac surgery]
Defined as death until one month postoperatively.
Secondary Outcome Measures
- Brain injury severity score on pre- and postoperative MRI [between birth and 1 month after cardiac surgery]
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 [between birth and 1 month after cardiac surgery]
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 [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 [at 3 months]
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).
- Neurodevelopment [at 24 months]
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).
- Executive functioning in comparison to healthy controls [at 24 months]
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).
- Quality of Life (scores and subscores): TNO-AZL TAPQoL [at 24 months]
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).
Eligibility Criteria
Criteria
Inclusion Criteria:
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Neonates with a prenatally or postnatally confirmed diagnosis of CCHD requiring (anticipated) cardiac surgery with CPB (within the first 4 weeks of life).
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Informed consent provided by both parents.
Exclusion Criteria:
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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.
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Doubt whether the aortic arch anomaly before birth requires cardiac surgery with CPB in the neonatal period.
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Gestational age below 36 weeks and/or birth weight less than 2000 gram - Surgery not requiring cardiopulmonary bypass.
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Patient considered "moribund".
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Decision for "comfort care only".
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | VU University Medical Center (VUmc) | Amsterdam | Netherlands | 1081 HV | |
| 2 | Academic Medical Center (AMC) | Amsterdam | Netherlands | 1105 AZ | |
| 3 | University Medical Center Groningen (UMCG) | Groningen | Netherlands | 9700 RB | |
| 4 | Leiden University Medical Center (LUMC) | Leiden | Netherlands | 2333 ZA | |
| 5 | Radboud University Medical Center Nijmegen (Radboudumc) | Nijmegen | Netherlands | 6525 GA | |
| 6 | Erasmus Medical Center Rotterdam (Erasmus MC) | Rotterdam | Netherlands | 3015 GD | |
| 7 | University Medical Center Utrecht (UMC Utrecht) | Utrecht | Netherlands | 3584 EA |
Sponsors and Collaborators
- dr. M.J.N.L. Benders
- ZonMw: The Netherlands Organisation for Health Research and Development
- University Medical Center Groningen
- Leiden University Medical Center
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Amsterdam UMC, location VUmc
- Erasmus Medical Center
- University Medical Center Nijmegen
- ACE Pharmaceuticals BV
Investigators
- Principal Investigator: Manon JNL Benders, Prof. MD PhD, University Medical Center Utrecht (UMC Utrecht)
- Principal Investigator: Johannes (Hans) MPJ Breur, MD PhD, University Medical Center Utrecht (UMC Utrecht)
- Study Director: Nicolaas (Koos) JG Jansen, MD PhD, University Medical Center Utrecht (UMC Utrecht)
- Study Director: Raymond Stegeman, MD, University Medical Center Utrecht (UMC Utrecht)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- METC UMCU 18-791
- 2017-004596-31