UCHL1 as a Biomarker of Brain Injury in Neonates and Infants Undergoing Cardiac Surgery: An Exploratory Study

As survival rates following pediatric cardiac surgery have improved, neurodevelopmental impairment has emerged as a significant long-term comorbidity. Neonates and infants are particularly vulnerable and are at the highest risk for neurodevelopmental impairment. Imaging study has identified new white matter injury in up to 20%-50% of this cohort postoperatively. Currently there is no clinical modality to accurately detect neurological events in real time during cardiac surgery. Brain imaging remains the gold standard for identifying cerebral injury, but it is only feasible postoperatively. In this study we intended to determine a plasma marker suitable to detect intraoperative brain injury by examining infant piglets undergoing cardiopulmonary bypass (CPB) and neonates/infants undergoing cardiac surgery on CPB. We compared two different CPB strategies; full-flow bypass alone and bypass involving circulatory arrest (CA) in infant piglets where CA was associated with post CPB neurodevelopmental impairment in our previous study. We found that ubiquitin C-terminal hydrolase L1 (UCHL1), a protein abundantly expressed in the neuronal body, was elevated in the blood after CA in infant piglets. CA group showed more proinflammatory profiles than full-flow bypass group. Histological analysis of piglet brain demonstrated that neurons underwent more apoptosis after CA, along with lower UCHL1 expression. Plasma proteomics analysis in infant piglets suggested the disruption of blood brain barrier (BBB) after CA compared to full-flow bypass. We hypothesized that UCHL1 could serve as a promising neurological injury marker in patients, too. We compared neonates and infants who underwent full-flow bypass alone and bypass involving CA/regional perfusion (RP) groups. Neonates and infants subjected to CA/RP had higher odds of having neurodevelopmental impairment compared to full-flow bypass group. CA/RP group showed more proinflammatory profiles than full-flow bypass group. Plasma proteomics analysis in neonates and infants also demonstrated similar findings in CA/RP arm compared to full-flow arm as we observed in piglets. UCHL1 level at the rewarming during CPB showed highest area under the curve (AUC) value of 0.7022 (95% CI 0.5692-0.8287). Overall, this study suggested UCHL1 to be a promising biomarker of brain injury associated with neurodevelopmental impairment following pediatric cardiac surgery involving CPB.