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Table 1 Secondary outcomes

From: 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

Domain Specific measurement Specific metric Method of aggregation Time point
Brain injury severity Brain injury severity score, determined by the assessment of brain injury on MRI in the deep gray matter, white matter, cortex, and cerebellum [39, 40]. Preoperative brain injury severity score, postoperative brain injury severity score, and change between pre- and postoperative brain injury severity score Mean (and SD) or median (and IQR) per group Preoperative (4–7 days after birth)
Postoperative (5–10 days after surgery or at least within 1 month after surgery)
White matter injury volume White matter injury volume (mm3), determined by manual segmentation with 3D-Slicer or ITK-SNAP 2.0 [41,42,43]. Preoperative white matter injury volume, postoperative white matter injury volume, and change between pre- and postoperative white matter injury volume Mean (and SD) or median (and IQR) per group Preoperative (4–7 days after birth)
Postoperative (5–10 days after surgery or at least within 1 month after surgery)
Echocardiographic systolic and diastolic function Echocardiographic assessment of global ventricular function (normal, mildly reduced, moderately reduced, severely reduced); ejection fraction (%); shortening fraction (%); ventricular dimensions (mm, Z-score corrected for BMI); velocity over the cardiac valves, i.e., Vpeak (m/s) and Vmean (m/s); cardiac valve insufficiency (no, mild, moderate, severe); longitudinal strain (%) and tissue Doppler imaging (myocardial deformation indices (m/s)); and systolic and diastolic pulmonic vein flow (m/s) [44]. Preoperative echocardiographic measurements, postoperative echocardiographic measurements, and change between pre- and postoperative echocardiographic measurements Distribution per group for categorical variables and mean (and SD) or median (and IQR) per group for continuous variables Preoperative (4–7 days after birth)
Postoperative (5–10 days after surgery or at least within 1 month after surgery)
Seizure activity Presence or absence of seizure activity on aEEG [45, 46]. Postnatal seizure activity and postoperative seizure activity Proportion of neonates with seizure activity per group Postnatal (until at least 24 h after birth)
Postoperative (until at least 48 h after surgery)
Regional cerebral oxygen saturation Regional cerebral oxygen saturation (%), lowest regional cerebral oxygen saturation (%), and duration of regional cerebral oxygen saturation < 45% (minutes) will be assessed by NIRS in intervals 0–3, 3–6, 6–12, 12–24, and 24–36 h after birth and 0–3, 3–6, 6–12, 12–24, 24–48, and 48–72 h after surgery [47, 48]. Postnatal regional cerebral oxygen saturation, postoperative regional cerebral oxygen saturation, and change between postnatal and postoperative regional cerebral oxygen saturation Mean (and SD) or median (and IQR) per group Postnatal (until at least 24 h after birth)
Postoperative (until at least 48 h after surgery)
General movements Assessment of general movements, using the motor optimality score [49,50,51]. Motor optimality score at 3 months Mean (and SD) or median (and IQR) per group 3 months
Motor, cognitive, and speech/language development Motor, cognitive, and language composite score of the Bayley-III-NL. An average Bayley-III-NL score is 100; one SD above or below the mean concerns 15 points [52]. Motor, cognitive, and language composite score at 24 months Mean (and SD) or median (and IQR) per group and proportion per group below 1 SD 24 months
Quality of life Parent-reported quality of life score using the TNO-AZL Preschool Children’s Health-Related Quality of Life questionnaire [53]. Parent-reported quality of life score at 24 months Mean (and SD) or median (and IQR) per group 24 months
Cost-effectiveness of allopurinol Questionnaires on the need for healthcare resources, productivity losses of parents, and expenses borne by families. Healthcare and societal costs will be determined with the Dutch guidelines for health economic evaluation. Healthcare and societal costs at 3 months; healthcare and societal costs at 24 months Mean (and SD) per group 3 months
24 months
Cost-effectiveness of allopurinol Length of hospitalization and intensive care stay (days) and costs associated with hospitalization using standard unit prices from Dutch guidelines for health economic evaluation. Healthcare costs Mean (and SD) per group 24 months
Cost-effectiveness of allopurinol Motor, cognitive, and language composite score of the Bayley-III-NL [52] and healthcare and societal costs. Healthcare and societal costs will be determined with the Dutch guidelines for health economic evaluation. Bayley-III-NL score, healthcare, and societal costs Cost per point improvement in neurodevelopmental outcome per group 24 months
Pharmacokinetic evaluation of allopurinol Allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid levels (mg/L) will be measured in blood samples collected around birth and surgery in 24 patients with a prenatal diagnosis [20, 32, 33, 54]. Allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid levels (mg/L) Mean (and SD) or median (and IQR) Postnatal (umbilical cord and 15–60 min, 4 h, 12 h, 13–14 h, 24 h, 36–48 h, and 96–168 h after birth)
Perioperative (0–3 h before dose 3, 1–3 h after dose 3, 0–1 h before dose 4, at the end of CPB, 4 h after surgery, 0–3 h before dose 5, 1–3 h after dose 5, and 48 h after surgery)
Redox and antioxidant state of allopurinol Enzyme-linked immunosorbent assay will be used to measure hypoxic tissue injury, overall redox and antioxidant state, lipid peroxidation, protein oxidation, and nitrosative state.
Mass spectrometry will be used to determine allopurinol, oxypurinol, non-protein bound iron, and xanthine oxidase levels (mg/L) [12].
Hypoxic tissue injury, overall redox and antioxidant state, lipid peroxidation, protein oxidation, and nitrosative state
Allopurinol, oxypurinol, non-protein bound iron, and xanthine oxidase levels (mg/L)
Mean (and SD) or median (and IQR) per group Postnatal (umbilical cord)
Perioperative (directly before surgery and 6 h, 1 day, 2 days, and 4 days after surgery)
  1. Abbreviations: aEEG Amplitude-integrated electroencephalography, Bayley-III-NL Bayley Scales of Infant and Toddler Development - Third Edition - Dutch Norms, BMI body mass index, CCHD critical congenital heart disease, CPB cardiopulmonary bypass, IQR interquartile range, MRI magnetic resonance imaging, NIRS near-infrared spectroscopy, SD standard deviation