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. 2023 Jul 28;49(9):1062–1078. doi: 10.1007/s00134-023-07165-x

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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Fig. 1 — The oxygen cascade and oxygen delivery to the brain. A The oxygen cascade is a multi-step process involving the movement of oxygen from the atmosphere to the mitochondria. Oxygen transport depends upon both convective and diffusive oxygen delivery along the oxygen cascade and subsequent utilisation by the mitochondria. B Air is drawn into the lungs, where the partial pressure of inspired oxygen (P_IO₂) is ~ 150 mmHg. Subsequent mixing with residual volume renders an alveolar partial pressure of oxygen (P_AO₂) of ~ 103 mmHg, where at the alveolar–capillary junction oxygen then diffuses from the alveoli to the blood whilst carbon dioxide diffuses from the blood to the alveoli. This diffusion process is associated with a slight reduction in the partial pressure of arterial oxygen (PaO₂) to approximately 98 mmHg. Thereafter, blood is pumped to the body by the heart. Importantly, cardiovascular (e.g., MAP), respiratory (e.g., PaO₂/PaCO₂), humoral (e.g., haemoglobin concentration, [Hb]), and microcirculatory (e.g., cerebrovascular resistance) factors influence CBF, which is determined by the integration of these physiologic factors and more [16]. Panel C depicts the neurovascular unit which is the anatomical and functional integration of cerebral microvasculature, peri-vascular glial cells and neurons, which ultimately maintains homeostasis in the brain parenchyma. D Convective oxygen delivery, denoted as (1), is determined by arterial oxygen content (CaO₂) and cerebral blood flow (CBF). (2) Following oxygen delivery to the cerebral capillary network, where the partial pressure of capillary oxygen (PCO₂) approximates 45 mmHg, oxygen diffusion from the cerebral vasculature to the cerebral parenchyma occurs. This diffusion process is determined by factors including the surface area for diffusion (A), the thickness of the diffusion barrier (T), and the pressure gradient for diffusion (ΔPO₂), and results in a brain tissue partial pressure of oxygen (PbtO₂) that is typically greater than 20 mmHg. Oxygen must then traverse the cytoplasm to reach the mitochondria, where the partial pressure of mitochondrial oxygen (P_MITOO₂) is 2–3 mmHg (estimation based upon measures of myoglobin saturation) [17]. (3) Finally, energetic homeostasis requires successfully utilising oxygen through aerobic mitochondrial respiration and generating adenosine triphosphate (ATP)