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. TRIAL REGISTRY: Preclinicaltrials.eu (PCTE0000272), published 2021-11-03.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

3rd Department of Internal Medicine General University Hospital Charles University Prague Czech Republic

Centre for Brain Research Indian Institute of Science Bangalore India

Clinical Neurochemistry Lab Sahlgrenska University Hospital Mölndal Sweden

Department of Biological Sciences and Pathobiology University of Veterinary Medicine Vienna Vienna Austria

Department of Clinical Sciences Anaesthesiology and Intensive Care Lund University 22184 Lund Sweden

Department of Clinical Sciences Neurology Lund University Lund Sweden

Department of Clinical Sciences Pathology Lund University Lund Sweden

Department of Emergency Medicine Medical University of Vienna Vienna Austria

Department of Genetics Pathology and Molecular Diagnostics Skåne University Hospital Lund Sweden

Department of Intensive and Perioperative Care Skåne University Hospital Lund Sweden

Department of Intensive and Perioperative Care Skåne University Hospital Malmö Sweden

Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK

Department of Neurology Skåne University Hospital Lund Sweden

Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine and Public Health Madison WI USA

Hong Kong Center for Neurodegenerative Diseases InnoHK Hong Kong China

Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Institute of Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

Neurodegenerative Disorder Research Center Division of Life Sciences and Medicine and Department of Neurology Institute On Aging and Brain Disorders University of Science and Technology of China and 1st Affiliated Hospital of USTC Hefei People's Republic of China

Paris Brain Institute ICM Pitié Salpêtrière Hospital Sorbonne University Paris France

Skåne University Hospital Lund Lund University and Clinical Studies Sweden Forum South Skåne University Hospital Lund Sweden

UK Dementia Research Institute at UCL London UK

Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health University of Wisconsin Madison Madison WI USA

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