BACKGROUND: Induced hypothermia post-cardiac arrest is neuroprotective in animal experiments, but few high-quality studies have been performed in larger animals with human-like brains. The neuroprotective effect of postischemic hypothermia has recently been questioned in human trials. Our aim is to investigate whether hypothermia post-cardiac arrest confers a benefit compared to normothermia in large adult animals. Our hypothesis is that induced hypothermia post cardiac arrest is neuroprotective and that the effect diminishes when delayed two hours. METHODS: Adult female pigs were anesthetized, mechanically ventilated and kept at baseline parameters including normothermia (38 °C). All animals were subjected to ten minutes of cardiac arrest (no-flow) by induced ventricular fibrillation, followed by four minutes of cardiopulmonary resuscitation with mechanical compressions, prior to the first countershock. Animals with sustained return of spontaneous circulation (systolic blood pressure >60 mmHg for ten minutes) within fifteen minutes from start of life support were included and randomized to three groups; immediate or delayed (2 h) intravenous cooling, both targeting 33 °C, or intravenously controlled normothermia (38 °C). Temperature control was applied for thirty hours including cooling time, temperature at target and controlled rewarming (0.5 °C/h). Animals were extubated and kept alive for seven days. The primary outcome measure is histological brain injury on day seven. Secondary outcomes include neurological and neurocognitive recovery, and the trajectory of biomarkers of brain injury. CONCLUSION: High-quality animal experiments in clinically relevant large animal models are necessary to close the gap of knowledge regarding neuroprotective effects of induced hypothermia after cardiac arrest.Trial registration: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

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

Department of Clinical Sciences Neurology Lund University Lund Sweden

Department of Clinical Sciences Pathology Lund University Lund Sweden

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 Neurology Skåne University Hospital Lund Sweden

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

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Gräsner J.-T., Herlitz J., Tjelmeland I.B.M., et al. European Resuscitation Council Guidelines 2021: Epidemiology of cardiac arrest in Europe. Resuscitation. 2021;161:61–79. doi: 10.1016/j.resuscitation.2021.02.007. PubMed DOI

Sandroni C., Cronberg T., Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med. 2021;47:1393–1414. doi: 10.1007/s00134-021-06548-2. PubMed DOI PMC

Laver S., Farrow C., Turner D., Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 2004;30:2126–2128. doi: 10.1007/s00134-004-2425-z. PubMed DOI

Hossmann K.-A., Lechtape-Grüter H., Hossmann V. The role of cerebral blood flow for the recovery of the brain after prolonged ischemia. Z Für Neurol. 1973;204:281–299. doi: 10.1007/BF00316009. PubMed DOI

Hoxworth J.M., Xu K., Zhou Y., Lust W.D., LaManna J.C. Cerebral metabolic profile, selective neuron loss, and survival of acute and chronic hyperglycemic rats following cardiac arrest and resuscitation. Brain Res. 1999;821:467–479. doi: 10.1016/S0006-8993(98)01332-8. PubMed DOI

Fischer M., Bockhorst K., Hoehn-Berlage M., Schmitz B., Hossmann K.-A. Imaging of the apparent diffusion coefficient for the evaluation of cerebral metabolic recovery after cardiac arrest. Magn Reson Imaging. 1995;13:781–790. doi: 10.1016/0730-725X(95)00030-K. PubMed DOI

Goldberg M., Choi D. Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci. 1993;13:3510–3524. doi: 10.1523/JNEUROSCI.13-08-03510.1993. PubMed DOI PMC

Xiong W., Hoesch R., Geocadin R. Post-cardiac arrest encephalopathy. Semin Neurol. 2011;31:216–225. doi: 10.1055/s-0031-1277991. PubMed DOI

Kiessling M., Stumm G., Xie Y., et al. Differential transcription and translation of immediate early genes in the gerbil hippocampus after transient global ischemia. J Cereb Blood Flow Metab. 1993;13:914–924. doi: 10.1038/jcbfm.1993.114. PubMed DOI

Bhalala U.S., Koehler R.C., Kannan S. Neuroinflammation and neuroimmune dysregulation after acute hypoxic-ischemic injury of developing brain. Front Pediatr. 2015;2 doi: 10.3389/fped.2014.00144. PubMed DOI PMC

Buunk G. Cerebral blood flow after cardiac arrest. Neth J Med. 2000;57:106–112. doi: 10.1016/S0300-2977(00)00059-0. PubMed DOI

Ameloot K., Genbrugge C., Meex I., et al. An observational near-infrared spectroscopy study on cerebral autoregulation in post-cardiac arrest patients: Time to drop ‘one-size-fits-all’ hemodynamic targets? Resuscitation. 2015;90:121–126. doi: 10.1016/j.resuscitation.2015.03.001. PubMed DOI

Björklund E., Lindberg E., Rundgren M., Cronberg T., Friberg H., Englund E. Ischaemic brain damage after cardiac arrest and induced hypothermia–a systematic description of selective eosinophilic neuronal death. A neuropathologic study of 23 patients. Resuscitation. 2014;85:527–532. doi: 10.1016/j.resuscitation.2013.11.022. PubMed DOI

Haglund M., Lindberg E., Englund E. Hippocampus and basal ganglia as potential sentinel sites for ischemic pathology after resuscitated cardiac arrest. Resuscitation. 2019;139:230–233. doi: 10.1016/j.resuscitation.2019.04.012. PubMed DOI

Polderman K.H. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37:S186–S202. doi: 10.1097/CCM.0b013e3181aa5241. PubMed DOI

Polderman K.H. Induced hypothermia and fever control for prevention and treatment of neurological injuries. The Lancet. 2008;371:1955–1969. doi: 10.1016/S0140-6736(08)60837-5. PubMed DOI

Schmidt O.I., Heyde C.E., Ertel W., Stahel P.F. Closed head injury—an inflammatory disease? Brain Res Rev. 2005;48:388–399. doi: 10.1016/j.brainresrev.2004.12.028. PubMed DOI

Leonov Y., Sterz F., Safar P., et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab. 1990;10:57–70. doi: 10.1038/jcbfm.1990.8. PubMed DOI

The Hypothermia After Cardiac Arrest Study Group Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;8 doi: 10.1056/NEJMoa012689. PubMed DOI

Bernard S.A., Jones B.M. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;7 PubMed

Nolan J.P., Morley P.T., Vanden Hoek T.L., et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation. 2003;108:118–121. doi: 10.1161/01.CIR.0000079019.02601.90. PubMed DOI

Deakin C.D., Nolan J.P., Soar J., et al. European Resuscitation Council guidelines for resuscitation 2010 section 4. Adult advanced life support. Resuscitation. 2010;81:1305–1352. doi: 10.1016/j.resuscitation.2010.08.017. PubMed DOI

Nielsen N., Wetterslev J., Cronberg T., et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369:2197–2206. doi: 10.1056/NEJMoa1310519. PubMed DOI

Dankiewicz J., Cronberg T., Lilja G., et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384:2283–2294. doi: 10.1056/NEJMoa2100591. PubMed DOI

Granfeldt A., Holmberg M.J., Nolan J.P., Soar J., Andersen L.W. Temperature control after adult cardiac arrest: an updated systematic review and meta-analysis. Resuscitation. 2023;191 doi: 10.1016/j.resuscitation.2023.109928. PubMed DOI

Sandroni C., Nolan J.P., Andersen L.W., et al. ERC-ESICM guidelines on temperature control after cardiac arrest in adults. Intensive Care Med. 2022;48:261–269. doi: 10.1007/s00134-022-06620-5. PubMed DOI

Olai H., Thornéus G., Watson H., et al. Meta-analysis of targeted temperature management in animal models of cardiac arrest. Intensive Care Med Exp. 2020;8:3. doi: 10.1186/s40635-019-0291-9. PubMed DOI PMC

Arrich J., Herkner H., Müllner D., Behringer W. Targeted temperature management after cardiac arrest. A systematic review and meta-analysis of animal studies. Resuscitation. 2021;162:47–55. doi: 10.1016/j.resuscitation.2021.02.002. PubMed DOI

Percie du Sert N., Hurst V., Ahluwalia A., et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLOS Biol. 2020;18 doi: 10.1371/journal.pbio.3000410. PubMed DOI PMC

Langhelle A., Nolan J., Herlitz J., et al. Recommended guidelines for reviewing, reporting, and conducting research on post-resuscitation care: the Utstein style. Resuscitation. 2005;66:271–283. doi: 10.1016/j.resuscitation.2005.06.005. PubMed DOI

Hardig B.M., Götberg M., Rundgren M., et al. Physiologic effect of repeated adrenaline (epinephrine) doses during cardiopulmonary resuscitation in the cath lab setting: a randomised porcine study. Resuscitation. 2016;101:77–83. doi: 10.1016/j.resuscitation.2016.01.032. PubMed DOI

Hannon J.P., Bossone C.A., Wade C.E. Normal physiological values for conscious pigs used in biomedical research. Lab Anim Sci. 1990;40:293–298. PubMed

Högler S., Sterz F., Sipos W., et al. Distribution of neuropathological lesions in pig brains after different durations of cardiac arrest. Resuscitation. 2010;81:1577–1583. doi: 10.1016/j.resuscitation.2010.07.005. PubMed DOI

Sipos W., Holzer M., Bayegan K., et al. A novel highly observer-independent neurologic exami- nation procedure for pigs in a model for cardiac arrest resuscitation. Wiener Tierarztliche Monatsschrift. 2008:11.

Fries M., Nolte K., Demir F., et al. Neurocognitive performance after cardiopulmonary resuscitation in pigs. Crit Care Med. 2008;36:842–847. doi: 10.1097/CCM.0B013E3181653041. PubMed DOI

Yuan W., Wu J.-Y., Zhao Y.-Z., et al. Comparison of early sequential hypothermia and delayed hypothermia on neurological function after resuscitation in a swine model. Am J Emerg Med. 2017;35:1645–1652. doi: 10.1016/j.ajem.2017.05.013. PubMed DOI

Hickey R.W., Ferimer H., Alexander H.L., et al. Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats. Crit Care Med. 2000;28 PubMed

Elbers A.R.W., Tielen M.J.M., Snijders J.M.A., Cromwijk W.A.J., Hunneman W.A. Epidemiological studies on lesions in finishing pigs in the Netherlands. I. Prevalence, seasonality and interrelationship. Prev Vet Med. 1992;14:217–231. doi: 10.1016/0167-5877(92)90018-B. DOI

Cleveland-Nielsen A., Nielsen E.O., Ersbøll A.K. Chronic pleuritis in Danish slaughter pig herds. Prev Vet Med. 2002;55:121–135. doi: 10.1016/S0167-5877(02)00089-2. PubMed DOI

Correia-Gomes C., Eze J.I., Borobia-Belsué J., et al. Voluntary monitoring systems for pig health and welfare in the UK: Comparative analysis of prevalence and temporal patterns of selected non-respiratory post mortem conditions. Prev Vet Med. 2017;146:1–9. doi: 10.1016/j.prevetmed.2017.07.007. PubMed DOI

Russell WMS. The Principles of Humane Experimental Technique. vol. 1959. Methuen, London; n.d.

Babini G., Grassi L., Russo I., et al. Duration of untreated cardiac arrest and clinical relevance of animal experiments: the relationship between the “no-flow” duration and the severity of post-cardiac arrest syndrome in a porcine model. Shock. 2018;49:205–212. doi: 10.1097/SHK.0000000000000914. PubMed DOI

National Research Council. Guide for the Care and Use of Laboratory Animals: Eighth Edition. vol. 2011. Washington, DC: The National Academies Press; n.d.

Skulec R., Truhlar A., Turek Z., et al. Comparison of cold crystalloid and colloid infusions for induction of therapeutic hypothermia in a porcine model of cardiac arrest. Crit Care Lond Engl. 2013;17:R242. doi: 10.1186/cc13068. PubMed DOI PMC