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Aim: To determine whether targeting mild hypercapnia (PaCO 2 7 kPa) would yield improved cerebral blood flow and metabolism compared to normocapnia (PaCO 2 5 kPa) with and without targeted temperature management to 33 °C (TTM33) in a porcine post-cardiac arrest model., Methods: 39 pigs were resuscitated after 10 minutes of cardiac arrest using cardiopulmonary bypass and randomised to TTM33 or no-TTM, and hypercapnia or normocapnia. TTM33 was managed with intravasal cooling. Animals were stabilized for 30 minutes followed by a two-hour intervention period. Hemodynamic parameters were measured continuously, and neuromonitoring included intracranial pressure (ICP), pressure reactivity index, cerebral blood flow, brain-tissue pCO 2 and microdialysis. Measurements are reported as proportion of baseline, and areas under the curve during the 120 min intervention period were compared., Results: Hypercapnia increased cerebral flow in both TTM33 and no-TTM groups, but also increased ICP (199% vs. 183% of baseline, p  = 0.018) and reduced cerebral perfusion pressure (70% vs. 84% of baseline, p  < 0.001) in no-TTM animals. Cerebral lactate (196% vs. 297% of baseline, p  < 0.001), pyruvate (118% vs. 152% of baseline, p  < 0.001), glycerol and lactate/pyruvate ratios were lower with hypercapnia in the TTM33 group, but only pyruvate (133% vs. 150% of baseline, p  = 0.002) was lower with hypercapnia among no-TTM animals., Conclusion: In this porcine post-arrest model, hypercapnia led to increased cerebral flow both with and without hypothermia, but also increased ICP and reduced cerebral perfusion pressure in no-TTM animals. The effects of hypercapnia were different with and without TTM.(Institutional protocol number: FOTS, id 14931)., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H. Karlsen: None C. Skåre: Research grant from Zoll Foundation, receieved May 2019. R.J Strand-Amundsen: Employed by Sensocure AS. M. Eriksen: None. V.M Skulberg: None. K. Sunde: None. T.I. Tønnessen: Shareholder, board member and medical advisor for Sensocure AS. T.M. Olasveengen: Board member for the Laerdal Foundation., (© 2024 The Author(s).)