Olof Persson Olof Persson Anna Valerianova Anna Valerianova Leos Tejkl Leos Tejkl Jan Bělohlávek Jan Bělohlávek Tobias Cronberg Tobias Cronberg Niklas Nielsen Niklas Nielsen Attila Frigyesi Attila Frigyesi Susann Ullén Susann Ullén Wolfgang Weihs Wolfgang Weihs Alexandra-Maria Stommel Alexandra-Maria Stommel Kaj Blennow Kaj Blennow Henrik Zetterberg Henrik Zetterberg Sandra Högler Sandra Högler Elisabet Englund Elisabet Englund Mikuláš Mlček Mikuláš Mlček Hans Friberg Hans Friberg Springer 2025 Background Induced hypothermia after cardiac arrest is neuroprotective in several animal models of cardiac arrest, but few high-quality studies have been conducted in larger animals. Recent clinical trials have questioned the beneficial effects of post-ischemic hypothermia. This study investigated whether immediate cooling or a 2-h delay in cooling to 33 °C after cardiac arrest was neuroprotective compared to controlled normothermia in large animals. Methods Young adult female swine were anesthetized and kept at normothermia (38 °C). All animals were subject to 10 min of cardiac arrest by ventricular fibrillation, followed by 4 min of cardiopulmonary resuscitation, before the first countershock. At 10 min of return of spontaneous circulation (ROSC), animals were included and randomized to receive immediate hypothermia (33 °C), 2-h delayed hypothermia (33 °C), or normothermia for 30 h, including both cooling and rewarming time. Animals were extubated and assessed for 7 days. The primary outcome was brain histopathology using a modified Histology Damage Score. Secondary outcomes were neurocognitive testing, neurologic deficit score, and biomarkers of brain injury. Results Among 42 animals, 33 were included; 11 in each arm, 23 survived until day 7. The modified Histology Damage Score was not significantly different between groups (p = 0.29). Neither neurocognitive testing nor neurologic deficit scores showed significant differences between the groups (p = 0.11 and p = 0.67, respectively). Neurofilament light chain (NfL) levels were significantly lower in the immediate hypothermia group at 48 h and on day 7 compared to the normothermia group (p = 0.0087, p = 0.012), but not in the delayed hypothermia group (p = 0.075, p = 0.33). Conclusion Our experimental model in large swine showed no neuropathological or functional protective effect of induced hypothermia after cardiac arrest, but NfL levels were lower in animals receiving immediately induced hypothermia, suggesting mitigation of neuronal injury. PDFDocument eng 2026-05-08T08:32:01.247198Z 2025 Cardiac Arrest Hypothermia Temperature Control Neuronal Damage Functional Outcome Neurofilament Light Chain (NfL) Swine 2649817 b application/pdf http://creativecommons.org/licenses/by/4.0/