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Objectives: To compare brain injury biomarker release levels between two different cardiopulmonary bypass (CPB) flow rates in elective cardiac surgery and to explore differences in postoperative delirium between groups and associations between age, sex, CPB time, oxygen levels, and near-infrared spectroscopy, and biomarker levels., Design: A randomized controlled substudy trial SETTING: Sahlgrenska University Hospital, Sweden PARTICIPANTS: Forty patients undergoing elective cardiac surgery with CPB INTERVENTION: Patients were assigned at random to either a standard (2.4 L/min/m 2 ) or a high (2.9 L/min/m 2 ) CPB flow rate., Measurements and Main Results: Glial fibrillary acidic protein, neurofilament light chain, total-tau, and phosphorylated-tau217 were sampled in plasma before anesthesia induction, after 60 minutes on CPB, and at 30 minutes, 24 hours, and 72 hours post-CPB. Mixed models for repeated measures were used to analyze differences in biomarker levels between groups and to assess relationships, which showed no differences between the 2 flow rate groups. There also was no difference in the occurrence of delirium between the 2 groups. Associations were found between age and increased neurofilament light chain levels. Female sex, oxygen delivery >330 mL/min/m 2 , and near-infrared spectroscopy level >60% were associated with lower biomarker levels., Conclusions: An increased flow rate did not have any significant effects on biomarker levels compared to a standard flow rate. Several associations were identified between treatment characteristics and biomarker levels. No difference in delirium was seen., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships that may be considered as potential competing interests. M.A. reports compensation for lectures and advisory boards from Biogen, Genzyme, and Novartis. L.L. reports consultancy honoraria from XVIVO Perfusion AB. K.B. is a founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, that includes board membership. Supported by the Swedish Research Council (Grants 2017-00915 and 2022-00732), the Swedish Alzheimer Foundation (Grants AF-930351, AF-939721, AF-968270, and AF-994551), Hjärnfonden Sweden (Grants FO2017-0243 and ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (ALFGBG-715986 and ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495), the Alzheimer's Association 2022-2025 Grant (SG-23-1038904 QC), La Fondation Recherche Alzheimer, and the Kirsten and Freddy Johansen Foundation. K.B. reports serving as a consultant and on advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; serving on data monitoring committees for Julius Clinical and Novartis; and participating in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics. He is a cofounder of Brain Biomarker Solutions in Gothenburg AB. H.Z. declares a financial interest in Biomarker Solutions in Gothenburg AB, which includes board membership. He is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (2023-00356, 2022-01018, and 2019-02397), the European Union's Horizon Europe research and innovation program under Grant 101053962, Swedish State Support for Clinical Research (ALFGBG-71320), the Alzheimer Drug Discovery Foundation (201809-2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C, and ADSF-24-1284328-C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2022-0270), the European Union's Horizon 2020 research and innovation program under Marie Skłodowska-Curie Grant 860197, the European Union Joint Programme–Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). He has served on scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB. R.O.B. reports receiving institutional research grants from Bristol-Myers Squibb, Endomag, SkyLineDx, and NeraCare GmbH; receiving speaker's honoraria from Roche, Pfizer, and Pierre-Fabre; and serving on advisory boards for Amgen, BD/BARD, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, and Sanofi Genzyme; and is a shareholder in SATMEG Ventures AB., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)