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

Overview

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.

Interventions

• 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.
• 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.

Primary outcome measures

• Relevant parenchymatous brain injury on postoperative MRI [Time frame: between birth and 1 month after cardiac surgery]
• Rate of children that are considered 'too unstable for postoperative MRI' [Time frame: between birth and 1 month after cardiac surgery]
• Incidence of mortality [Time frame: between birth and 1 month after cardiac surgery]

Secondary outcome measures (9)

• Brain injury severity score on pre- and postoperative MRI [Time frame: between birth and 1 month after cardiac surgery]
• Volume of hypoxic-ischemic brain injury on pre- and postoperative MRI [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 [Time frame: at 3 months]
• Neurodevelopment [Time frame: at 24 months]
• Quality of Life (scores and subscores): TNO-AZL TAPQoL [Time frame: at 24 months]

Eligibility criteria

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.
• Decision for "comfort care only".

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Netherlands · 4 centers

• University Medical Center Groningen (UMCG) — Groningen
• Radboud University Medical Center Nijmegen (Radboudumc) — Nijmegen
• Erasmus Medical Center Rotterdam (Erasmus MC) — Rotterdam
• University Medical Center Utrecht (UMC Utrecht) — Utrecht

Publications

• Stegeman R, Nijman M, Breur JMPJ, Groenendaal F, Haas F, Derks JB, Nijman J, van Beynum IM, Taverne YJHJ, Bogers AJJC, Helbing WA, de Boode WP, Bos AF, Berger RMF, Accord RE, Roes KCB, de Wit GA, Jansen NJG, Benders MJNL; CRUCIAL trial consortium. CeRebrUm and CardIac Protection with ALlopurinol in Neonates with Critical Congenital Heart Disease Requiring Cardiac Surgery with Cardiopulmonary Bypas PMID 35197082
• Chu WY, Nijman M, Stegeman R, Breur JMPJ, Jansen NJG, Nijman J, van Loon K, Koomen E, Allegaert K, Benders MJNL, Dorlo TPC, Huitema ADR; CRUCIAL trial consortium. Population Pharmacokinetics and Target Attainment of Allopurinol and Oxypurinol Before, During, and After Cardiac Surgery with Cardiopulmonary Bypass in Neonates with Critical Congenital Heart Disease. Clin Pharmacokinet. 2024 Aug;63(8): PMID 39147988

Identifiers

NCT: NCT04217421 · METC UMCU 18-791 · 2017-004596-31

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗