CeRebrUm and CardIac Protection with ALlopurinol in Neonates with Critical Congenital Heart Disease Requiring Cardiac Surgery with Cardiopulmonary Bypass (CRUCIAL): study protocol of a phase III, randomized, quadruple-blinded, placebo-controlled, Dutch multicenter trial

Raymond Stegeman, Maaike Nijman, Johannes M P J Breur, Floris Groenendaal, Felix Haas, Jan B Derks, Joppe Nijman, Ingrid M van Beynum, Yannick J H J Taverne, Ad J J C Bogers, Willem A Helbing, Willem P de Boode, Arend F Bos, Rolf M F Berger, Ryan E Accord, Kit C B Roes, G Ardine de Wit, Nicolaas J G Jansen, Manon J N L Benders, CRUCIAL trial consortium, Raymond Stegeman, Maaike Nijman, Johannes M P J Breur, Floris Groenendaal, Felix Haas, Jan B Derks, Joppe Nijman, Ingrid M van Beynum, Yannick J H J Taverne, Ad J J C Bogers, Willem A Helbing, Willem P de Boode, Arend F Bos, Rolf M F Berger, Ryan E Accord, Kit C B Roes, G Ardine de Wit, Nicolaas J G Jansen, Manon J N L Benders, CRUCIAL trial consortium

Abstract

Background: Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury.

Methods: This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol.

Discussion: This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates.

Trial registration: EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020.

Keywords: Allopurinol; Brain injury; Cardiac function; Congenital heart disease; Neonate; Neurodevelopmental outcome.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Administration schedule of study medication in both groups. A Administration schedule in prenatally diagnosed neonates (prenatal group). B Administration schedule in postnatally diagnosed neonates (postnatal group). CCHD, critical congenital heart disease; CPB, cardiopulmonary bypass; h, hours; min, minutes
Fig. 2
Fig. 2
Participant timeline. Black circles (●) indicate neonates with a prenatal CCHD diagnosis. White circles (○) indicate neonates with a postnatal CCHD diagnosis. *In included subjects from the Erasmus Medical Center Rotterdam and University Medical Center Utrecht. **In the first 24 subjects with a prenatal CCHD diagnosis in UMC Utrecht. aEEG, amplitude-integrated electroencephalography; Bayley-III-NL, Bayley Scales of Infant and Toddler Development - Third Edition - Dutch Norms; CCHD, critical congenital heart disease; h, hours; HTA, health technology assessment; MRI, magnetic resonance imaging; NIRS, near-infrared spectroscopy; TAPQoL, TNO-AZL preschool children’s health-related quality of life

References

    1. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890–1900.
    1. Oster ME, Lee KA, Honein MA, Riehle-Colarusso T, Shin M, Correa A. Temporal trends in survival among infants with critical congenital heart defects. Pediatrics [Internet] 2013;131(5):e1502–e1508.
    1. Snookes SH, Gunn JK, Eldridge BJ, Donath SM, Hunt RW, Galea MP, et al. A systematic review of motor and cognitive outcomes after early surgery for congenital heart disease. Pediatrics. 2010;125(4):e818–e827.
    1. Latal B. Neurodevelopmental outcomes of the child with congenital heart disease. Clin Perinatol. 2016;43(1):173–185.
    1. Sun L, Macgowan CK, Sled JG, Yoo SJ, Manlhiot C, Porayette P, et al. Reduced fetal cerebral oxygen consumption is associated with smaller brain size in fetuses with congenital heart disease. Circulation. 2015;131(15):1313–1323.
    1. Claessens NHP, Kelly CJ, Counsell SJ, Benders MJNL. Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease. Dev Med Child Neurol. 2017;59(9):894–902.
    1. Mebius MJ, Kooi EMW, Bilardo CM, Bos AF. Brain injury and neurodevelopmental outcome in congenital heart disease: a systematic review. Pediatrics. 2017;140(1):e20164055.
    1. Claessens NHP, Chau V, de Vries LS, Jansen NJG, Au-Young SH, Stegeman R, et al. Brain injury in infants with critical congenital heart disease: insights from two clinical cohorts with different practice approaches. J Pediatr. 2019;215:75–82.e2.
    1. Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Semin Neonatol [Internet] 2000;5(1):3–16.
    1. Ferriero DM. Neonatal brain injury. N Engl J Med. 2004;351(19):1985–1995.
    1. Hagberg H, David Edwards A, Groenendaal F. Perinatal brain damage: the term infant. Neurobiol Dis. 2016;92(Pt A):102–112.
    1. Taverne YJHJ, Bogers AJJC, Duncker DJ, Merkus D. Reactive oxygen species and the cardiovascular system. Oxid Med Cell Longev. 2013;2013:862423.
    1. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med [Internet] 1985;312(3):159–163.
    1. van Bel F, Groenendaal F. Drugs for neuroprotection after birth asphyxia: pharmacologic adjuncts to hypothermia. Semin Perinatol. 2016;40(3):152–159.
    1. Hirsch JC, Jacobs ML, Andropoulos D, Austin EH, Jacobs JP, Licht DJ, et al. Protecting the infant brain during cardiac surgery: a systematic review. Ann Thorac Surg [Internet]. 2012;94(4):1365–1373.
    1. Wypij D, Jonas RA, Bellinger DC, Del Nido PJ, Mayer JE, Bacha EA, et al. The effect of hematocrit during hypothermic cardiopulmonary bypass in infant heart surgery: results from the combined Boston hematocrit trials. J Thorac Cardiovasc Surg. 2008;135(2):355–360.
    1. Jonas RA, Wypij D, Roth SJ, Bellinger DC, Visconti KJ, du Plessis AJ, et al. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg. 2003;126(6):1765–1774.
    1. Newburger JW, Jonas RA, Soul J, Kussman BD, Bellinger DC, Laussen PC, et al. Randomized trial of hematocrit 25% versus 35% during hypothermic cardiopulmonary bypass in infant heart surgery. J Thorac Cardiovasc Surg [Internet] 2008;135(2):347–54, 354 e1-4.
    1. Stegeman R, Lamur KD, van den Hoogen A, Breur JMPJ, Groenendaal F, Jansen NJG, et al. Neuroprotective drugs in infants with severe congenital heart disease: a systematic review. Front Neurol. 2018;9(JUL) 10.3389/fneur.2018.00521.
    1. Day RO, Graham GG, Hicks M, McLachlan AJ, Stocker SL, Williams KM. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet [Internet] 2007;46(8):623–644.
    1. Shadid M, Buonocore G, Groenendaal F, Moison R, Ferrali M, Berger HM, et al. Effect of deferoxamine and allopurinol on non-protein-bound iron concentrations in plasma and cortical brain tissue of newborn lambs following hypoxia-ischemia. Neurosci Lett [Internet] 1998;248(1):5–8.
    1. Moorhouse PC, Grootveld M, Halliwell B, Quinlan JG, Gutteridge JM. Allopurinol and oxypurinol are hydroxyl radical scavengers. FEBS Lett [Internet] 1987;213(1):23–28.
    1. Marro PJ, Mishra OP, Delivoria-Papadopoulos M. Effect of allopurinol on brain adenosine levels during hypoxia in newborn piglets50. Brain Res [Internet] 2006;1073–1074:444–450.
    1. Talwar S, Selvam MS, Makhija N, Lakshmy R, Choudhary SK, Sreenivas V, et al. Effect of administration of allopurinol on postoperative outcomes in patients undergoing intracardiac repair of tetralogy of Fallot. J Thorac Cardiovasc Surg [Internet] 2018;155(1):335–343.
    1. Annink KV, Franz AR, Derks JB, Rudiger M, Bel F, van Benders MJNL. Allopurinol: old drug, new indication in neonates? Curr Pharm Des. 2017;23(38):5935–5942.
    1. Clancy RR, McGaurn SA, Goin JE, Hirtz DG, Norwood WI, Gaynor JW, et al. Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest. Pediatrics. 2001;108(1):61–70.
    1. Van Bel F, Shadid M, Moison RM, Dorrepaal CA, Fontijn J, Monteiro L, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. 1998;101(2):185–193.
    1. Benders MJNL, Bos AF, Rademaker CMA, Rijken M, Torrance HL, Groenendaal F, et al. Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006;91(3):F163–F165.
    1. Gunes T, Ozturk MA, Koklu E, Kose K, Gunes I. Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Pediatr Neurol. 2007;36(1):17–24.
    1. Kaandorp JJ, Benders MJNL, Schuit E, Rademaker CMA, Oudijk MA, Porath MM, et al. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015;100(3):F216–F223.
    1. Torrance HL, Benders MJ, Derks JB, Rademaker CMA, Bos AF, Van Den Berg P, et al. Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B. Pediatrics. 2009;124(1):350–357.
    1. McGaurn SP, Davis LE, Krawczeniuk MM, Murphy JD, Jacobs ML, Norwood WI, et al. The pharmacokinetics of injectable allopurinol in newborns with the hypoplastic left heart syndrome. Pediatrics [Internet] 1994;94(6 Pt 1):820–823.
    1. Marro PJ, Baumgart S, Delivoria-Papadopoulos M, Zirin S, Corcoran L, McGaurn SP, et al. Purine metabolism and inhibition of xanthine oxidase in severely hypoxic neonates going onto extracorporeal membrane oxygenation. Pediatr Res [Internet] 1997;41(4 Pt 1):513–520.
    1. Algra SO, Haas F, Poskitt KJ, Groenendaal F, Schouten ANJ, Jansen NJG, et al. Minimizing the risk of preoperative brain injury in neonates with aortic arch obstruction. J Pediatr [Internet] 2014;165(6):1116–1122.e3.
    1. Beca J, Gunn J, Coleman L, Hope A, Whelan L-C, Gentles T, et al. Pre-operative brain injury in newborn infants with transposition of the great arteries occurs at rates similar to other complex congenital heart disease and is not related to balloon atrial septostomy. J Am Coll Cardiol. 2009;53(19):1807–1811.
    1. Claessens NHP, Algra SO, Ouwehand TL, Jansen NJG, Schappin R, Haas F, et al. Perioperative neonatal brain injury is associated with worse school-age neurodevelopment in children with critical congenital heart disease. Dev Med Child Neurol. 2018; 10.1111/dmcn.13747.
    1. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:1–42.
    1. Tavakkoli F. Review of the role of mannitol in the therapy of children. 18th Expert Comm Sel use Essent Med Mannitol Rev. 2011;3–13
    1. Weeke LC, Groenendaal F, Mudigonda K, Blennow M, Lequin MH, Meiners LC, et al. A novel magnetic resonance imaging score predicts neurodevelopmental outcome after perinatal asphyxia and therapeutic hypothermia. J Pediatr. 2018;192:33–40.e2.
    1. Stegeman R, Feldmann M, Claessens NHP, Jansen NJG, Breur JMPJ, de Vries LS, et al. A uniform description of perioperative brain MRI findings in infants with severe congenital heart disease: results of a European collaboration. AJNR Am J Neuroradiol. 2021; 10.3174/ajnr.A7328.
    1. Murphy K, van der Aa NE, Negro S, Groenendaal F, de Vries LS, Viergever MA, et al. Automatic quantification of ischemic injury on diffusion-weighted MRI of neonatal hypoxic ischemic encephalopathy. Neuroimage Clin [Internet] 2017;14:222–232.
    1. Fedorov A, Beichel R, Kalpathy-Cramer J, Finet J, Fillion-Robin J-C, Pujol S, et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging. 2012;30(9):1323–1341.
    1. Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):1116–1128.
    1. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr. 2010;23(5):465–467.
    1. Claessens NHP, Noorlag L, Weeke LC, Toet MC, Breur JMPJ, Algra SO, et al. Amplitude-integrated electroencephalography for early recognition of brain injury in neonates with critical congenital heart disease. J Pediatr. 2018;202:199–205.e1.
    1. Mebius MJ, Oostdijk NJE, Kuik SJ, Bos AF, Berger RMF, Bilardo CM, et al. Amplitude-integrated electroencephalography during the first 72 h after birth in neonates diagnosed prenatally with congenital heart disease. Pediatr Res. 2018;83(4):798–803.
    1. Claessens NHP, Jansen NJG, Breur JMPJ, Algra SO, Stegeman R, Alderliesten T, et al. Postoperative cerebral oxygenation was not associated with new brain injury in infants with congenital heart disease. J Thorac Cardiovasc Surg. 2019;158(3):867–877.e1.
    1. Mebius MJ, van der Laan ME, Verhagen EA, Roofthooft MT, Bos AF, Kooi EM. Cerebral oxygen saturation during the first 72 h after birth in infants diagnosed prenatally with congenital heart disease. Early Hum Dev. 2016;103:199–203.
    1. Einspieler C, Bos AF, Libertus ME, Marschik PB. The general movement assessment helps us to identify preterm infants at risk for cognitive dysfunction. Front Psychol. 2016;7:406.
    1. Einspieler C, Bos AF, Krieber-Tomantschger M, Alvarado E, Barbosa VM, Bertoncelli N, et al. Cerebral palsy: early markers of clinical phenotype and functional outcome. J Clin Med. 2019;8(10):1616.
    1. Mebius MJ, Bilardo CM, Kneyber MCJ, Modestini M, Ebels T, Berger RMF, et al. Onset of brain injury in infants with prenatally diagnosed congenital heart disease. PLoS One. 2020;15(3):e0230414.
    1. Craig AA, Adam JG, Bayley N. Bayley Scales of Infant and Toddler Development–Third Edition. San Antonio, TX: Harcourt Assessment. J Psychoeduc Assess. 2007;25(2):180–198.
    1. Fekkes M, Theunissen NC, Brugman E, Veen S, Verrips EG, Koopman HM, et al. Development and psychometric evaluation of the TAPQOL: a health-related quality of life instrument for 1-5-year-old children. Qual life Res an Int J Qual life Asp Treat care Rehabil. 2000;9(8):961–972.
    1. van Kesteren C, Benders MJNL, Groenendaal F, van Bel F, Ververs FFT, Rademaker CMA. Population pharmacokinetics of allopurinol in full-term neonates with perinatal asphyxia. Ther Drug Monit. 2006;28(3):339–344.
    1. Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The results database--update and key issues. N Engl J Med. 2011;364(9):852–860.
    1. Saldanha IJ, Dickersin K, Wang X, Li T. Outcomes in Cochrane systematic reviews addressing four common eye conditions: an evaluation of completeness and comparability. PLoS One. 2014;9(10):e109400.
    1. Erdogan D, Tayyar S, Uysal BA, Icli A, Karabacak M, Ozaydin M, et al. Effects of allopurinol on coronary microvascular and left ventricular function in patients with idiopathic dilated cardiomyopathy. Can J Cardiol. 2012;28(6):721–727.
    1. Gaynor JW, Stopp C, Wypij D, Andropoulos DB, Atallah J, Atz AM, et al. Neurodevelopmental outcomes after cardiac surgery in infancy. Pediatrics [Internet] 2015;135(5):816–825.
    1. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet (London, England) 2005;365(9460):663–670.
    1. McCoy CE. Understanding the Intention-to-treat principle in randomized controlled trials. West J Emerg Med. 2017;18(6):1075–1078.
    1. Algra SO, Jansen NJG, van der Tweel I, Schouten ANJ, Groenendaal F, Toet M, et al. Neurological injury after neonatal cardiac surgery: a randomized, controlled trial of 2 perfusion techniques. Circulation. 2014;129(2):224–233.
    1. Schmidt B, Gillie P, Caco C, Roberts J, Roberts R. Do sick newborn infants benefit from participation in a randomized clinical trial? J Pediatr [Internet] 1999;134(2):151–155.
    1. Bakker MK, Bergman JEH, Krikov S, Amar E, Cocchi G, Cragan J, et al. Prenatal diagnosis and prevalence of critical congenital heart defects: an international retrospective cohort study. BMJ Open [Internet] 2019;9(7):e028139.
    1. Fan X, Kavelaars A, Heijnen CJ, Groenendaal F, van Bel F. Pharmacological neuroprotection after perinatal hypoxic-ischemic brain injury. Curr Neuropharmacol. 2010;8(4):324–334.
    1. Kaandorp JJ, van Bel F, Veen S, Derks JB, Groenendaal F, Rijken M, et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F162–F166.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner