Branched-chain amino acids accumulate and glutamate decreases in cerebral interstitial fluid following cardiopulmonary bypass in neonatal swine

Objectives Dysregulated metabolism of the branched-chain amino acids (BCAAs—leucine, isoleucine, valine) can cause irreversible neurologic injury in neonates. BCAA metabolism is tightly linked to glutamate synthesis. Glutamate excitotoxicity has been implicated as a mechanism of neuronal injury following deep hypothermic circulatory arrest. This investigation explores glutamate and BCAA homeostasis following continuous cardiopulmonary bypass (CPB). Methods Fifteen neonatal swine underwent 3 hrs of continuous CPB and five animals each were survived for 12 hrs, 18 hrs, or 24 hrs post-CPB (N = 15). Three additional piglets underwent similar sham procedures and identical monitoring for 3 hrs without CPB (N = 3). Liquid chromatography-mass spectrometry was used to quantify metabolites in plasma, extracellular cerebral interstitial fluid (CIF), and cortical brain tissue samples collected at similar timepoints of analysis. Between-group and multiple comparisons tests were performed to identify differences in metabolomic profiles post-CPB. Results Glutamate concentrations in CIF were lower than baseline at 12–24 hrs post-CPB (P = 0.015), but tended to increase in cortical brain tissue compared to sham animals (P = 0.095). In contrast, BCAAs were significantly elevated in extracellular CIF following CPB, and increased relative to plasma concentrations at 24 hrs post-CPB (leucine: P = 0.079; isoleucine: P = 0.044; valine: P = 0.043). However, BCAAs in cortical brain tissue were unchanged or tended to decrease compared to sham animals at 12–24 hrs CPB (leucine: P = 0.607; isoleucine: P = 0.067; valine: P = 0.912). Conclusions Following continuous CPB, BCAAs increase and glutamate decreases in extracellular CIF. Further investigations are warranted to elucidate how CPB and various neuroprotection strategies affect regional and cell type-specific changes in cerebral metabolism during critical periods of neurodevelopment.