Quantity of assimilated oxygen on 100 gr. of cerebral tissue

The quantity of consumed oxygen per 100 g brain tissue is associated with a complex cause, involved in the redox processes, lipid peroxidation reactions, and with a state of thyroid blood circulation regulation. Thyroid blood circulation determines the transportation of oxygen and its consumption by inner organs due to the activation of thyroid hormones T3 and T4. This index depends on the activation or inactivation of organ oxygen consumption. This value averages 2.5-3.5 ml/100 g tissue for adults and 3.5-6 ml/100 g tissue for children.

Oxygen Delivery and Autoregulation

The weight of the brain is only 2% of the human body, but cerebral tissue uses 25% of the glucose and about 20% of the oxygen delivered to function normally [14]. Oxygen consumption is 3.5 mL of oxygen/100 g tissue/1 min; therefore, the regulation of blood flow and delivery of oxygen to cerebral tissue is crucial for brain function [15]. Importantly, 75–80% of the energy consumed by neurons is used at the synapses to restore the neuronal membrane potentials lost during depolarization [16]. The continuous supply of oxygen to the brain occurs via arterial blood and is transported to brain tissue by diffusion. Diffusion is linked to the oxygen conductivity of cerebral tissue, determined by the geometry of capillaries (distance and area) and the metabolism of tissue (oxygen gradient from capillary to tissue) [17]. Extraction of oxygen is inversely proportional to blood flow (when metabolism is constant) and directly proportional to metabolism (when flow is constant) and the area between tissue and capillaries. Thus, a reduction in oxygen delivery increases oxygen extraction. It should be noted that when cerebral blood flow (CBF) is reduced by 50–60%, the consequent elevation of oxygen extraction is insufficient to maintain proper cerebral oxygenation and a constant cerebral metabolic rate of oxygen (CMRO2) [18]. Thus, cerebral oxygen delivery is determined by blood oxygen content and cerebral blood flow. In physiological conditions, total blood flow in the brain is constant because of the contribution of the large arteries to vascular resistance, as well as the impact of the parenchymal arterioles on considerable basal tone.

Autoregulation of cerebral blood flow is the mechanism that enables the brain to maintain relatively constant blood flow through changes in perfusion pressure [19]. In a normotensive, physiological state, the ensuing cerebral perfusion pressure (CPP) is in the range of 60 to 160 mmHg, and CBF is maintained at 50 mL per 100 g of brain tissue per minute. Outside of this range, autoregulation is lost, and CBF starts to be dependent on MAP in a linear mode [20]. A drop of CPP below the lower limit of 50 mmHg results in cerebral ischemia [21]. This reduction of CBF is compensated for by elevated oxygen extraction from the blood.

The individualization of care by targeting optimal, near to cerebral autoregulation (CA)-guided CPP is connected with improved outcomes in TBI patients [22]. It is worth remembering that combined brain tissue oxygen with ICP/CCP-guided therapy strongly ameliorates favorable long-term outcomes [23]. In addition, in a recent meta-analysis, Xie et al. documented that this combined therapy did not present any effects on mortality, ICP/CPP and length of stay of patients after TBI [23].

Over a physiological range of partial oxygen pressure (PaO₂) (75–100 mmHg; 7–13.33 kPa), PaO₂ has little effect on global CBF as long as it does not fall below 50 mmHg (6.67 kPa). This is because CBF is connected to the arterial content of oxygen rather than PaO₂. The form of the hemoglobin–oxygen dissociation curve indicates that the arterial content of oxygen is comparatively stable over the discussed PaO₂ range [24].

The primary gradient determining the oxygen level in the brain may be enhanced by a gradient-independent mechanism of cerebral vessel tone changes and increases in CBF during functional neural activation (neurovascular coupling) [25,26]. The main role of this mechanism is to transport higher levels of oxygen in advance of the elevated consumption during neuronal activation [27].

Impairment of cerebral perfusion and metabolism following brain injury has been documented repeatedly. Unfavorable outcomes after brain injury are connected with hypoperfusion and decreased glucose metabolism and CMRO₂ [28]. Recent data have documented a connection between CMRO₂ and Glasgow Coma Score (GCS) after traumatic brain injury [29,30,31,32]. Soustiel et al. demonstrated that in TBI patients, CBF is somewhat reduced during the first 24 h, and greater hypovolemia is observed following poor outcomes. Importantly, a decrease in CMRO₂ and the cerebral rate of glucose metabolism (CMRG) correlates with worse outcomes [32].

Oxygen Consumption

Oxygen is transported to the cerebral cells by blood diffusion from the capillary to the mitochondria, until it is consumed in the mitochondria as part of oxidative metabolism. CMRO₂ is the rate of consumption and energy homeostasis in the brain and in healthy, awake people, averages 3.3 mL/100 g/min [33]. It is related to CBF. Under elevated metabolic demand, the cerebral vasculature dilates to supply an appropriate increase in CBF.

Importantly, with elevated neural activity, CMRO₂ also rises [34,35]. In a normal, unstimulated brain, energy is mostly provided by glucose oxidation. Nevertheless, the metabolic rates of the oxygen-to-glucose ratio, CMRO₂/CMR(glc), called the oxygen-to-glucose index (OGI), increase during activation and diverge from the textbook value of 6. In addition, the levels of lactates in the brain increase during sensory (e.g., visual) stimulation [34]. This oxidative metabolism yields more energy as compared to glycolysis, but precise measurements of this process are limited [36]. Mitochondria present a high metabolic activity and a critical role in aerobic energy production, and their main function is the production of adenosine triphosphate (ATP) through oxidative phosphorylation.

Mitochondrial dysfunction is a major factor in the occurrence of cell damage. Successful resuscitation during ischemia/reperfusion demands the reestablishment of aerobic metabolism by reperfusion of oxygenated blood. Mitochondria play a fundamental role as effectors of reperfusion injury. Damage to the organelle impairs oxidative phosphorylation and elimination of cytochrome c in the cytosol. The main mechanisms are oxidative stress and Ca²⁺ overload [36].

Disturbances in oxygen delivery stop electron flow and interrupt the generation of the “proton motive force” important in ATP production mentioned above. Of course, cells may produce ATP anaerobically by glycolysis. However, this process is less effective, insufficient for metabolic demands, and the final products are lactates.

Hypoxia

The brain is one of the most sensitive organs to hypoxia, reoxygenation and oxidative stress. As mentioned above, the brain has very high metabolic oxygen requirements, and it is highly susceptible to hypoxic damage (Table 1).

Table 1

Potentially effect of disorders in oxygen delivery to the brain on selected pathways and factors. Up arrows indicate the direction of the mechanism that may be intensified to varying degrees, depending on the causative factor. The number of arrows defines the intensity of the processes.

Clinical implications of hypoxia:

• Reduced brain tissue oxygenation is a predictor of poor outcome following severe traumatic brain injury.
• Hypoxic–ischemic brain injury (HIBI) is associated with significant mortality and morbidity [91].
• The LOCO₂ study documented that targeting lower PaO₂ improves outcomes in patients with acute respiratory distress syndrome (ARDS) [92].
• The brain tissue oxygen tension (PbtO₂) is crucial, the second monitored variable after ICP, representing multimodality monitoring in TBI patients [11,93].
• Secondary hypoxia is connected with extended production of cytokines in CSF and superior elevation of serum biomarkers such as myelin-basic protein (MBP) and S100 [94].
• The MBP, S100 and neuron-specific enolase (NSE) biomarkers are more elevated in patients with hypoxia and unfavorable outcomes (Extended Glasgow Outcome Coma Score (GOSE) 1–4) [94]
• HIBI, as a two-hit model, is an effect of primary and secondary ischemic/hypoxic damage predisposing to overall devastating severe injury of neurovascular units [91]
• Secondary brain hypoxia is connected with de novo neuronal and astroglial injury. Importantly, secondary hypoxia is associated with cerebral proinflammatory response but not parallel cerebral endothelial injury [91].
• Protocols based on PbtO₂ and ICP monitoring significantly decrease cerebral hypoxia time after TBI [95].
• Acute intermittent hypoxia (AIH) and task-specific training (TST) may synergistically improve motor functions after central nervous system injury [96].

Clinical implications of hyperoxia:

• Hyperoxia is associated with higher mortality and worse short-term functional outcomes, especially in patients who receive uncontrolled oxygen delivery during the first 24 h after brain injury (probably because of hyperoxia-induced oxygen-free radical toxicity with or without vasoconstriction) [123].
• Potential toxicity of a high oxygen concentration (patients receiving FiO₂ of more than 0.6).
• Previous studies documented that higher inspired oxygen concentration is associated with acute lung injury, with mild to severe diffuse alveolar damage (DAD) [124].
• High oxygen levels within 72 h after aneurysmal rupture is an uninfluenced predictor of cerebral vasospasm [125].
• In addition, liberal oxygen therapy increased 30-day mortality compared with conservative therapy [126].
• Controversial high-dose oxygen therapy recommendations to reduce surgical site infections (SSIs) by World Health Organization global guidelines for the prevention of surgical site infection [127].
• Hyperoxemia may reduce cardiac output and increase systemic vascular resistance in patients with cardiovascular failure [128].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9698645/

1. Semenza G.L. Life with Oxygen. Science. 2007;318:62–64. doi: 10.1126/science.1147949. [PubMed] [CrossRef] [Google Scholar]

2. Özugur S., Kunz L., Straka H. Relationship between oxygen consumption and neuronal activity in a defined neural circuit. BMC Biol. 2020;18:76. doi: 10.1186/s12915-020-00811-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Roy C.S., Sherrington C.S. On the Regulation of the Blood-supply of the Brain. J. Physiol. 1890;11:85–158. doi: 10.1113/jphysiol.1890.sp000321. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

4. Maas A.I.R., Menon D.K., Adelson P.D., Andelic N., Bell M.J., Belli A., Bragge P., Brazinova A., Büki A., Chesnut R.M., et al. Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16:987–1048. doi: 10.1016/S1474-4422(17)30371-X. [PubMed] [CrossRef] [Google Scholar]

5. Chesnut R.M., Marshall L.F., Klauber M.R., Blunt B.A., Baldwin N., Eisenberg H.M., Jane J.A., Marmarou A., Foulkes M.A. The Role of Secondary Brain Injury in Determining Outcome from Severe Head Injury. J. Trauma Inj. Infect. Crit. Care. 1993;34:216–222. doi: 10.1097/00005373-199302000-00006. [PubMed] [CrossRef] [Google Scholar]

6. Volpi P.C., Robba C., Rota M., Vargiolu A., Citerio G. Trajectories of early secondary insults correlate to outcomes of traumatic brain injury: Results from a large, single centre, observational study. BMC Emerg. Med. 2018;18:52. doi: 10.1186/s12873-018-0197-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

7. Maloney-Wilensky E., Gracias V., Itkin A., Hoffman K., Bloom S., Yang W., Christian S., Leroux P.D. Brain tissue oxygen and outcome after severe traumatic brain injury: A systematic review. Crit. Care Med. 2009;37:2057–2063. doi: 10.1097/CCM.0b013e3181a009f8. [PubMed] [CrossRef] [Google Scholar]

8. Jeremitsky E., Omert L., Dunham C.M., Protetch J., Rodriguez A. Harbingers of Poor Outcome the Day after Severe Brain Injury: Hypothermia, Hypoxia, and Hypoperfusion. J. Trauma Inj. Infect. Crit. Care. 2003;54:312–319. doi: 10.1097/01.TA.0000037876.37236.D6. [PubMed] [CrossRef] [Google Scholar]

9. Bogossian E.G., Diaferia D., Djangang N.N., Menozzi M., Vincent J.-L., Talamonti M., Dewitte O., Peluso L., Barrit S., Al Barajraji M., et al. Brain tissue oxygenation guided therapy and outcome in non-traumatic subarachnoid hemorrhage. Sci. Rep. 2021;11:16235. doi: 10.1038/s41598-021-95602-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

10. Martini R.P., Deem S., Treggiari M.M. Targeting Brain Tissue Oxygenation in Traumatic Brain Injury. Respir. Care. 2012;58:162–172. doi: 10.4187/respcare.01942. [PubMed] [CrossRef] [Google Scholar]

11. Chesnut R., Aguilera S., Buki A., Bulger E., Citerio G., Cooper D.J., Arrastia R.D., Diringer M., Figaji A., Gao G., et al. A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: The Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC) Intensiv. Care Med. 2020;46:919–929. doi: 10.1007/s00134-019-05900-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

12. Rakhit S., Nordness M.F., Lombardo S.R., Cook M., Smith L., Patel M.B. Management and Challenges of Severe Traumatic Brain Injury. Semin. Respir. Crit. Care Med. 2021;42:127–144. doi: 10.1055/s-0040-1716493. [PubMed] [CrossRef] [Google Scholar]

13. Sekhon M.S., Gooderham P., Menon D.K., Brasher P.M.A., Foster D., Cardim D., Czosnyka M., Smielewski P., Gupta A.K., Ainslie P.N., et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit. Care Med. 2019;47:960–969. doi: 10.1097/CCM.0000000000003745. [PubMed] [CrossRef] [Google Scholar]

14. Hyder F., Rothman D.L., Bennett M.R. Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels. Proc. Natl. Acad. Sci. USA. 2013;110:3549–3554. doi: 10.1073/pnas.1214912110. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

15. Rink C., Khanna S. Significance of Brain Tissue Oxygenation and the Arachidonic Acid Cascade in Stroke. Antioxid. Redox Signal. 2011;14:1889–1903. doi: 10.1089/ars.2010.3474. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

16. Harris J.J., Jolivet R., Attwell D. Synaptic Energy Use and Supply. Neuron. 2012;75:762–777. doi: 10.1016/j.neuron.2012.08.019. [PubMed] [CrossRef] [Google Scholar]

17. Gjedde A. Advances in Experimental Medicine and Biology. Springer; Boston, MA, USA: 2005. The pathways of oxygen in brain. I. Delivery and metabolism of oxygen; p. 566. [PubMed] [Google Scholar]

18. Bain A.R., Morrison S., Ainslie P.N. Cerebral oxygenation and hyperthermia. Front. Physiol. 2014;5:92. doi: 10.3389/fphys.2014.00092. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

19. Paulson O.B., Strandgaard S., Edvinsson L. Cerebral autoregulation. Cerebrovasc. Brain Metab. Rev. 1990;2:161–192. [PubMed] [Google Scholar]

20. Cipolla M.J., Osol G. Vascular Smooth Muscle Actin Cytoskeleton in Cerebral Artery Forced Dilatation. Stroke. 1998;29:1223–1228. doi: 10.1161/01.STR.29.6.1223. [PubMed] [CrossRef] [Google Scholar]

21. Baron J.-C. Perfusion Thresholds in Human Cerebral Ischemia: Historical Perspective and Therapeutic Implications. Cerebrovasc. Dis. 2001;11((Suppl. 1)):2–8. doi: 10.1159/000049119. [PubMed] [CrossRef] [Google Scholar]

22. Tas J., Beqiri E., van Kaam R.C., Czosnyka M., Donnelly J., Haeren R.H., van der Horst I.C., Hutchinson P.J., van Kuijk S.M., Liberti A.L., et al. Targeting Autoregulation-Guided Cerebral Perfusion Pressure after Traumatic Brain Injury (COGiTATE): A Feasibility Randomized Controlled Clinical Trial. J. Neurotrauma. 2021;38:2790–2800. doi: 10.1089/neu.2021.0197. [PubMed] [CrossRef] [Google Scholar]

23. Xie Q., Wu H.-B., Yan Y.-F., Liu M., Wang E.-S. Mortality and Outcome Comparison Between Brain Tissue Oxygen Combined with Intracranial Pressure/Cerebral Perfusion Pressure–Guided Therapy and Intracranial Pressure/Cerebral Perfusion Pressure–Guided Therapy in Traumatic Brain Injury: A Meta-Analysis. World Neurosurg. 2017;100:118–127. doi: 10.1016/j.wneu.2016.12.097. [PubMed] [CrossRef] [Google Scholar]

24. McDowall D.G. Interrelationships between blood oxygen tensions and cerebral blood flow. Oxyg. Meas. Blood Tissues. 1966;4:205–219. [PubMed] [Google Scholar]

25. Attwell D., Buchan A.M., Charpak S., Lauritzen M.J., MacVicar B.A., Newman E.A. Glial and neuronal control of brain blood flow. Nature. 2010;468:232–243. doi: 10.1038/nature09613. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

26. Muoio V., Persson P.B., Sendeski M.M. The neurovascular unit—concept review. Acta Physiol. 2014;210:790–798. doi: 10.1111/apha.12250. [PubMed] [CrossRef] [Google Scholar]

27. Sokoloff L. Energetics of Functional Activation in Neural Tissues. Neurochem. Res. 1999;24:321–329. doi: 10.1023/A:1022534709672. [PubMed] [CrossRef] [Google Scholar]

28. Hattori N., Huang S.-C., Wu H.-M., Yeh E., Glenn T.C., Vespa P.M., McArthur D., E Phelps M., A Hovda D., Bergsneider M. Correlation of regional metabolic rates of glucose with glasgow coma scale after traumatic brain injury. J. Nucl. Med. 2003;44:1709. [PubMed] [Google Scholar]

29. Bergsneider M., Hovda D.A., Lee S.M., Kelly D.F., McArthur D., Vespa P.M., Lee J.H., Huang S.-C., Martin N., Phelps M.E., et al. Dissociation of Cerebral Glucose Metabolism and Level of Consciousness During the Period of Metabolic Depression Following Human Traumatic Brain Injury. J. Neurotrauma. 2000;17:389–401. doi: 10.1089/neu.2000.17.389. [PubMed] [CrossRef] [Google Scholar]

30. Bergsneider M., Hovda D.A., Shalmon E., Kelly D.F., Vespa P.M., Martin N.A., Phelps M.E., McArthur D.L., Caron M.J., Kraus J.F., et al. Cerebral hyperglycolysis following severe traumatic brain injury in humans: A positron emission tomography study. J. Neurosurg. 1997;86:241–251. doi: 10.3171/jns.1997.86.2.0241. [PubMed] [CrossRef] [Google Scholar]

31. Obrist W.D., Langfitt T.W., Jaggi J.L., Cruz J., Gennarelli T.A. Cerebral blood flow and metabolism in comatose patients with acute head injury: Relationship to intracranial hypertension. J. Neurosurg. 1984;61:241–253. doi: 10.3171/jns.1984.61.2.0241. [PubMed] [CrossRef] [Google Scholar]

32. Soustiel J.F., Glenn T.C., Shik V., Boscardin J., Mahamid E., Zaaroor M. Monitoring of Cerebral Blood Flow and Metabolism in Traumatic Brain Injury. J. Neurotrauma. 2005;22:955–965. doi: 10.1089/neu.2005.22.955. [PubMed] [CrossRef] [Google Scholar]

33. Cold G.E. Cerebral Metabolic Rate of Oxygen (CMRO2) in the Acute Phase of Brain Injury. Acta Anaesthesiol. Scand. 1978;22:249–256. doi: 10.1111/j.1399-6576.1978.tb01299.x. [PubMed] [CrossRef] [Google Scholar]

34. Shulman R.G., Hyder F., Rothman D.L. Lactate efflux and the neuroenergetic basis of brain function. NMR Biomed. 2001;14:389–396. doi: 10.1002/nbm.741. [PubMed] [CrossRef] [Google Scholar]

35. Thompson Jeffrey K., Peterson Matthew R., Freeman Ralph D. Single-Neuron Activity and Tissue Oxygenation in the Cerebral Cortex. Science. 2003;299:1070–1072. doi: 10.1126/science.1079220. [PubMed] [CrossRef] [Google Scholar]

36. Hyder F., Kida I., Behar K.L., Kennan R.P., Maciejewski P.K., Rothman D.L. Quantitative functional imaging of the brain: Towards mapping neuronal activity by BOLD fMRI. NMR Biomed. 2001;14:413–431. doi: 10.1002/nbm.733. [PubMed] [CrossRef] [Google Scholar]

37. Hochachka P.W., Buck L.T., Doll C.J., Land S.C. Unifying theory of hypoxia tolerance: Molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc. Natl. Acad. Sci. USA. 1996;93:9493–9498. doi: 10.1073/pnas.93.18.9493. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

38. Boyer P.D. The Atp Synthase—A Splendid Molecular Machine. Annu. Rev. Biochem. 1997;66:717–749. doi: 10.1146/annurev.biochem.66.1.717. [PubMed] [CrossRef] [Google Scholar]

39. Wu I.C., Ohsawa I., Fuku N., Tanaka M. Metabolic analysis of 13C-labeled pyruvate for noninvasive assessment of mitochondrial function. Ann. N. Y. Acad. Sci. 2010;1201:111–120. doi: 10.1111/j.1749-6632.2010.05636.x. [PubMed] [CrossRef] [Google Scholar]

40. Wellen K.E., Thompson C.B. Cellular metabolic stress: Considering how cells respond to nutrient excess. Mol. Cell. 2010;40:323–332. doi: 10.1016/j.molcel.2010.10.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

41. Sas K., Robotka H., Toldi J., Vécsei L. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J. Neurol. Sci. 2007;257:221–239. doi: 10.1016/j.jns.2007.01.033. [PubMed] [CrossRef] [Google Scholar]

42. Diringer M.N., Yundt K., Videen T.O., Adams R.E., Zazulia A.R., Deibert E., Aiyagari V., Dacey R.G., Grubb R.L., Powers W.J. No reduction in cerebral metabolism as a result of early moderate hyperventilation following severe traumatic brain injury. J. Neurosurg. 2000;92:7–13. doi: 10.3171/jns.2000.92.1.0007. [PubMed] [CrossRef] [Google Scholar]

43. Zhang Z., Guo Q., Wang E. Hyperventilation in neurological patients: From physiology to outcome evidence. Curr. Opin. Anesthesiol. 2019;32:568–573. doi: 10.1097/ACO.0000000000000764. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

44. Mas A., Saura P., Joseph D., Blanch L., Baigorri F., Artigas A., Fernandez R. Effect of acute moderate changes in PaCO2 on global hemodynamics and gastric perfusion. Crit. Care Med. 2000;28:360–365. doi: 10.1097/00003246-200002000-00012. [PubMed] [CrossRef] [Google Scholar]

45. Howarth C., Sutherland B.A., Choi H.B., Martin C., Lind B.L., Khennouf L., LeDue J.M., Pakan J.M., Ko R.W., Ellis-Davies G., et al. A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain. J. Neurosci. 2017;37:2403–2414. doi: 10.1523/JNEUROSCI.0005-16.2016. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

46. Carney N., Totten A.M., O’Reilly C., Ullman J.S., Hawryluk G.W., Bell M.J., Bratton S.L., Chesnut R., Harris O.A., Kissoon N., et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017;80:6–15. doi: 10.1227/NEU.0000000000001432. [PubMed] [CrossRef] [Google Scholar]

47. Oddo M., Bösel J. Monitoring of brain and systemic oxygenation in neurocritical care patients. Neurocritical Care. 2014;21:103–120. doi: 10.1007/s12028-014-0024-6. [PubMed] [CrossRef] [Google Scholar]

48. Chen R., Lai U.H., Zhu L., Singh A., Ahmed M., Forsyth N.R. Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors. Front. Cell Dev. Biol. 2018;6:132. doi: 10.3389/fcell.2018.00132. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

49. Banasiak K.J., Xia Y., Haddad G.G. Mechanisms underlying hypoxia-induced neuronal apoptosis. Prog. Neurobiol. 2000;62:215–249. doi: 10.1016/S0301-0082(00)00011-3. [PubMed] [CrossRef] [Google Scholar]

50. Chang E., Hornick K., Fritz K.I., Mishra O.P., Delivoria-Papadopoulos M. Effect of Hyperoxia on Cortical Neuronal Nuclear Function and Programmed Cell Death Mechanisms. Neurochem. Res. 2007;32:1142–1149. doi: 10.1007/s11064-007-9282-4. [PubMed] [CrossRef] [Google Scholar]

51. Serocki M., Bartoszewska S., Janaszak-Jasiecka A., Ochocka R.J., Collawn J.F., Bartoszewski R. miRNAs regulate the HIF switch during hypoxia: A novel therapeutic target. Angiogenesis. 2018;21:183–202. doi: 10.1007/s10456-018-9600-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

52. Koh M.Y., Lemos R., Liu X., Powis G. The hypoxia-associated factor switches cells from HIF-1α-to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 2011;71:4015–4027. doi: 10.1158/0008-5472.CAN-10-4142. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

53. Masamoto K., Tanishita K. Oxygen Transport in Brain Tissue. J. Biomech. Eng. 2009;131:074002. doi: 10.1115/1.3184694. [PubMed] [CrossRef] [Google Scholar]

54. Taguchi H., Heistad D.D., Kitazono T., Faraci F.M. ATP-sensitive K+ channels mediate dilatation of cerebral arterioles during hypoxia. Circ. Res. 1994;74:1005–1008. doi: 10.1161/01.RES.74.5.1005. [PubMed] [CrossRef] [Google Scholar]

55. Johnston A.J., Steiner L.A., Gupta A.K., Menon D.K. Cerebral oxygen vasoreactivity and cerebral tissue oxygen reactivity. Br. J. Anaesth. 2003;90:774–786. doi: 10.1093/bja/aeg104. [PubMed] [CrossRef] [Google Scholar]

56. Xu K., LaManna J.C. Chronic hypoxia and the cerebral circulation. J. Appl. Physiol. 2006;100:725–730. doi: 10.1152/japplphysiol.00940.2005. [PubMed] [CrossRef] [Google Scholar]

57. Boero J.A., Ascher J., Arregui A., Rovainen C., Woolsey T.A. Increased brain capillaries in chronic hypoxia. J. Appl. Physiol. 1999;86:1211–1219. doi: 10.1152/jappl.1999.86.4.1211. [PubMed] [CrossRef] [Google Scholar]

58. Torres-Cuevas I., Parra-Llorca A., Sánchez-Illana Á., Nuñez-Ramiro A., Kuligowski J., Cháfer-Pericás C., Cernada M., Escobar J., Vento M. Oxygen and oxidative stress in the perinatal period. Redox Biol. 2017;12:674–681. doi: 10.1016/j.redox.2017.03.011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

59. Rocha-Ferreira E., Hristova M. Plasticity in the Neonatal Brain following Hypoxic-Ischaemic Injury. Neural Plast. 2016;2016:4901014. doi: 10.1155/2016/4901014. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

60. Sekhon M.S., Ainslie P.N., Griesdale D.E. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: A “two-hit” model. Crit. Care. 2017;21:90. doi: 10.1186/s13054-017-1670-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

61. Chen H., Yoshioka H., Kim G.S., Jung J.E., Okami N., Sakata H., Maier C.M., Narasimhan P., Goeders C.E., Chan P.H. Oxidative Stress in Ischemic Brain Damage: Mechanisms of Cell Death and Potential Molecular Targets for Neuroprotection. Antioxid. Redox Signal. 2011;14:1505–1517. doi: 10.1089/ars.2010.3576. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

62. Coimbra-Costa D., Alva N., Duran M., Carbonell T., Rama R. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol. 2017;12:216–225. doi: 10.1016/j.redox.2017.02.014. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

63. Peña F., Ramirez J.-M. Hypoxia-induced changes in neuronal network properties. Mol. Neurobiol. 2005;32:251–283. doi: 10.1385/MN:32:3:251. [PubMed] [CrossRef] [Google Scholar]

64. Majmundar A.J., Wong W.J., Simon M.C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell. 2010;40:294–309. doi: 10.1016/j.molcel.2010.09.022. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

65. Dengler V.L., Galbraith M.D., Espinosa J.M. Transcriptional regulation by hypoxia inducible factors. Crit. Rev. Biochem. Mol. Biol. 2014;49:1–15. doi: 10.3109/10409238.2013.838205. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

66. Chávez J.C., Agani F., Pichiule P., LaManna J.C. Expression of hypoxia-inducible factor-1α in the brain of rats during chronic hypoxia. J. Appl. Physiol. 2000;89:1937–1942. doi: 10.1152/jappl.2000.89.5.1937. [PubMed] [CrossRef] [Google Scholar]

67. Lukyanova L.D., Kirova Y.I. Mitochondria-controlled signaling mechanisms of brain protection in hypoxia. Front. Neurosci. 2015;9:320. doi: 10.3389/fnins.2015.00320. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

68. Brix B., Mesters J.R., Pellerin L., Jöhren O. Endothelial cell-derived nitric oxide enhances aerobic glycolysis in astrocytes via HIF-1α-mediated target gene activation. J. Neurosci. 2012;32:9727–9735. doi: 10.1523/JNEUROSCI.0879-12.2012. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

69. Koh M.Y., Powis G. Passing the baton: The HIF switch. Trends Biochem. Sci. 2012;37:364–372. doi: 10.1016/j.tibs.2012.06.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

70. Luo W., Zhong J., Chang R., Hu H., Pandey A., Semenza G.L. Hsp70 and CHIP Selectively Mediate Ubiquitination and Degradation of Hypoxia-inducible Factor (HIF)-1α but Not HIF-2α 2. J. Biol. Chem. 2010;285:3651–3663. doi: 10.1074/jbc.M109.068577. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

71. Liu Y.V., Semenza G.L. RACK1 vs. HSP90: Competition for HIF-1α degradation vs. stabilization. Cell Cycle. 2007;6:656–659. doi: 10.4161/cc.6.6.3981. [PubMed] [CrossRef] [Google Scholar]

72. Liu Y.V., Baek J.H., Zhang H., Diez R., Cole R.N., Semenza G.L. RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α Mol. Cell. 2007;25:207–217. doi: 10.1016/j.molcel.2007.01.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

73. Ravi R., Mookerjee B., Bhujwalla Z.M., Sutter C.H., Artemov D., Zeng Q., Dillehay L.E., Madan A., Semenza G.L., Bedi A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α Genes Dev. 2000;14:34–44. doi: 10.1101/gad.14.1.34. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

74. Bhattacharya R., SenBanerjee S., Lin Z., Mir S., Hamik A., Wang P., Mukherjee P., Mukhopadhyay D., Jain M.K. Inhibition of Vascular Permeability Factor/Vascular Endothelial Growth Factor-mediated Angiogenesis by the Kruppel-like Factor KLF2. J. Biol. Chem. 2005;280:28848–28851. doi: 10.1074/jbc.C500200200. [PubMed] [CrossRef] [Google Scholar]

75. Kawanami D., Mahabeleshwar G.H., Lin Z., Atkins G.B., Hamik A., Haldar S.M., Maemura K., LaManna J.C., Jain M.K. Kruppel-like Factor 2 Inhibits Hypoxia-inducible Factor 1α Expression and Function in the Endothelium. J. Biol. Chem. 2009;284:20522–20530. doi: 10.1074/jbc.M109.025346. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

76. Lee Y., Ahn C., Han J., Choi H., Kim J., Yim J., Lee J., Provost P., Rådmark O., Kim S., et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415–419. doi: 10.1038/nature01957. [PubMed] [CrossRef] [Google Scholar]

77. Davis G.M., Haas M.A., Pocock R. MicroRNAs: Not “fine-tuners” but key regulators of neuronal development and function. Front. Neurol. 2015;6:245. doi: 10.3389/fneur.2015.00245. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

78. Xiao S., Ma Y., Zhu H., Sun H., Yin Y., Feng G. miRNA functional synergistic network analysis of mice with ischemic stroke. Neurol. Sci. 2015;36:143–148. doi: 10.1007/s10072-014-1904-4. [PubMed] [CrossRef] [Google Scholar]

79. Chan S.Y., Loscalzo J. MicroRNA-210: A unique and pleiotropic hypoxamir. Cell Cycle. 2010;9:1072–1083. doi: 10.4161/cc.9.6.11006. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

80. Yang G.-Y., Zeng L., Liu J., Wang Y., Wang L., Weng S., Tang Y., Zheng C., Cheng Q., Chen S. MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front. Biosci. 2011;E3:1265–1272. doi: 10.2741/e330. [PubMed] [CrossRef] [Google Scholar]

81. Qiu J., Zhou X.-Y., Zhou X.-G., Cheng R., Liu H.-Y., Li Y. Neuroprotective effects of microRNA-210 on hypoxic-ischemic encephalopathy. BioMed Res. Int. 2013;2013:350419. doi: 10.1155/2013/350419. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

82. Tan K.S., Armugam A., Sepramaniam S., Lim K.Y., Setyowati K.D., Wang C.W., Jeyaseelan K. Expression Profile of MicroRNAs in Young Stroke Patients. PLoS ONE. 2009;4:e7689. doi: 10.1371/journal.pone.0007689. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

83. Minhas G., Mathur D., Ragavendrasamy B., Sharma N.K., Paanu V., Anand A. Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies. Front. Neurosci. 2017;11:386. doi: 10.3389/fnins.2017.00386. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

84. Bobryshev P., Bagaeva T., Filaretova L. Ischemic preconditioning attenuates gastric ischemia-reperfusion injury through involvement of glucocorticoids. J. Physiol. Pharmacol. 2009;60((Suppl. 7)):155–160. [PubMed] [Google Scholar]

85. Rybnikova E.A., Mironova V.I., Pivina S.G., Ordyan N.E., Tulkova E.I., Samoilov M.O. Hormonal Mechanisms of Neuroprotective Effects of the Mild Hypoxic Preconditioning in Rats. 1st ed. Springer Nature BV; Berlin/Heidelberg, Germany: 2008. p. 239. [PubMed] [Google Scholar]

86. Davis C., Hackett P. Advances in the prevention and treatment of high altitude illness. Emerg. Med. Clin. 2017;35:241–260. doi: 10.1016/j.emc.2017.01.002. [PubMed] [CrossRef] [Google Scholar]

87. Rybnikova E., Mironova V., Pivina S., Tulkova E., Ordyan N., Nalivaeva N., Turner A., Samoilov M. Involvement of the hypothalamic-pituitary-adrenal axis in the antidepressant-like effects of mild hypoxic preconditioning in rats. Psychoneuroendocrinology. 2007;32:813–823. doi: 10.1016/j.psyneuen.2007.05.010. [PubMed] [CrossRef] [Google Scholar]

88. Vanderhaeghen T., Beyaert R., Libert C. Bidirectional Crosstalk Between Hypoxia Inducible Factors and Glucocorticoid Signalling in Health and Disease. Front. Immunol. 2021;12:684085. doi: 10.3389/fimmu.2021.684085. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

89. Kodama T., Shimizu N., Yoshikawa N., Makino Y., Ouchida R., Okamoto K., Hisada T., Nakamura H., Morimoto C., Tanaka H. Role of the Glucocorticoid Receptor for Regulation of Hypoxia-dependent Gene Expression. J. Biol. Chem. 2003;278:33384–33391. doi: 10.1074/jbc.M302581200. [PubMed] [CrossRef] [Google Scholar]

90. Lim W., Park C., Shim M.K., Lee Y.H., Lee Y.M., Lee Y. Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1α expression through the induction of glucocorticoid-induced leucine zipper. Br. J. Pharmacol. 2014;171:735–745. doi: 10.1111/bph.12491. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

91. Hoiland R.L., Ainslie P.N., Wellington C.L., Cooper J., Stukas S., Thiara S., Foster D., Fergusson N.A., Conway E.M., Menon D.K., et al. Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post–Cardiac Arrest. Circ. Res. 2021;129:583–597. doi: 10.1161/CIRCRESAHA.121.319157. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

92. Barrot L., Asfar P., Mauny F., Winiszewski H., Montini F., Badie J., Quenot J.-P., Pili-Floury S., Bouhemad B., Louis G., et al. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N. Engl. J. Med. 2020;382:999–1008. doi: 10.1056/NEJMoa1916431. [PubMed] [CrossRef] [Google Scholar]

93. Bardt T.F., Unterberg A.W., Härtl R., Kiening K.L., Schneider G.H., Lanksch W.R. Monitoring of brain tissue PO2 in traumatic brain injury: Effect of cerebral hypoxia on outcome. In: Marmarou A., Bullock R., Avezaat C., Baethmann A., Becker D., Brock M., Hoff J., Nagai H., Reulen H.-J., Teasdale G., editors. Intracranial Pressure and Neuromonitoring in Brain Injury. Springer; Vienna, Austria: 1998. pp. 153–156. [PubMed] [Google Scholar]

94. Yan E.B., Satgunaseelan L., Paul E., Bye N., Nguyen P., Agyapomaa D., Kossmann T., Rosenfeld J.V., Morganti-Kossmann C. Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury. J. Neurotrauma. 2013;31:618–629. doi: 10.1089/neu.2013.3087. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

95. Okonkwo D.O., Shutter L., Moore C., Temkin N.R., Puccio A.M., Madden C.J., Andaluz N., Chesnut R., Bullock M.R., Grant G.A., et al. Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II. Crit. Care Med. 2017;45:1907–1914. doi: 10.1097/CCM.0000000000002619. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

96. Welch J.F., Sutor T.W., Vose A.K., Perim R.R., Fox E.J., Mitchell G.S. Synergy between Acute Intermittent Hypoxia and Task-Specific Training. Exerc. Sport Sci. Rev. 2020;48:125–132. doi: 10.1249/JES.0000000000000222. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

97. Gore A., Muralidhar M., Espey M.G., Degenhardt K., Mantell L.L. Hyperoxia sensing: From molecular mechanisms to significance in disease. J. Immunotoxicol. 2010;7:239–254. doi: 10.3109/1547691X.2010.492254. [PubMed] [CrossRef] [Google Scholar]

98. Bin-Jaliah I., Haffor A.-S. Ultrastructural Morphological Alterations during Hyperoxia Exposure in Relation to Glutathione Peroxidase Activity and Free Radicals Productions in the Mitochondria of the Cortical Brain. Int. J. Morphol. 2018;36:1310–1315. doi: 10.4067/S0717-95022018000401310. [CrossRef] [Google Scholar]

99. Chong Z.-Z., Lin S.H., Li F., Maiese K. The Sirtuin Inhibitor Nicotinamide Enhances Neuronal Cell Survival During Acute Anoxic Injury Through AKT, BAD, PARP, and Mitochondrial Associated. Curr. Neurovascular Res. 2005;2:271–285. doi: 10.2174/156720205774322584. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

100. Terraneo L., Paroni R., Bianciardi P., Giallongo T., Carelli S., Gorio A., Samaja M. Brain adaptation to hypoxia and hyperoxia in mice. Redox Biol. 2017;11:12–20. doi: 10.1016/j.redox.2016.10.018. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

101. Felderhoff-Mueser U., Bittigau P., Sifringer M., Jarosz B., Korobowicz E., Mahler L., Piening T., Moysich A., Grune T., Thor F., et al. Oxygen causes cell death in the developing brain. Neurobiol. Dis. 2004;17:273–282. doi: 10.1016/j.nbd.2004.07.019. [PubMed] [CrossRef] [Google Scholar]

102. Zhang Y., Park T.S., Gidday J.M. Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation. Am. J. Physiol. Heart Circ. Physiol. 2007;292:H2573–H2581. doi: 10.1152/ajpheart.01098.2006. [PubMed] [CrossRef] [Google Scholar]

103. Nayak G.H., Prentice H.M., Milton S.L. Neuroprotective signaling pathways are modulated by adenosine in the anoxia tolerant turtle. J. Cereb. Blood Flow Metab. 2011;31:467–475. doi: 10.1038/jcbfm.2010.109. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

104. Mao M., Zhiling W., Hui Z., Shengfu L., Dan Y., Jiping H. Cellular levels of TrkB and MAPK in the neuroprotective role of BDNF for embryonic rat cortical neurons against hypoxia in vitro. Int. J. Dev. Neurosci. 2005;23:515–521. [PubMed] [Google Scholar]

105. Digicaylioglu M., Bichet S., Marti H.H., Wenger R.H., Rivas L.A., Bauer C., Gassmann M. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc. Natl. Acad. Sci. USA. 1995;92:3717–3720. doi: 10.1073/pnas.92.9.3717. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

106. Sanchez P.E., Fares R.P., Risso J.-J., Bonnet C., Bouvard S., Le-Cavorsin M., Georges B., Moulin C., Belmeguenai A., Bodennec J., et al. Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons. Proc. Natl. Acad. Sci. USA. 2009;106:9848–9853. doi: 10.1073/pnas.0901840106. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

107. Sakanaka M., Wen T.-C., Matsuda S., Masuda S., Morishita E., Nagao M., Sasaki R. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. USA. 1998;95:4635–4640. doi: 10.1073/pnas.95.8.4635. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

108. Kato S., Aoyama M., Kakita H., Hida H., Kato I., Ito T., Goto T., Hussein M.H., Sawamoto K., Togari H., et al. Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury. J. Neurosci. Res. 2011;89:1566–1574. doi: 10.1002/jnr.22702. [PubMed] [CrossRef] [Google Scholar]

109. Brown G.C. Nitric oxide and neuronal death. Nitric Oxide. 2010;23:153–165. doi: 10.1016/j.niox.2010.06.001. [PubMed] [CrossRef] [Google Scholar]

110. Garry P.S., Ezra M., Rowland M.J., Westbrook J., Pattinson K.T.S. The role of the nitric oxide pathway in brain injury and its treatment—From bench to bedside. Exp. Neurol. 2015;263:235–243. doi: 10.1016/j.expneurol.2014.10.017. [PubMed] [CrossRef] [Google Scholar]

111. Cheng A., Wang S., Cai J., Rao M.S., Mattson M.P. Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev. Biol. 2003;258:319–333. doi: 10.1016/S0012-1606(03)00120-9. [PubMed] [CrossRef] [Google Scholar]

112. Li S.-T., Pan J., Hua X.-M., Liu H., Shen S., Liu J.-F., Li B., Tao B.-B., Ge X.-L., Wang X.-H., et al. Endothelial Nitric Oxide Synthase Protects Neurons against Ischemic Injury through Regulation of Brain-Derived Neurotrophic Factor Expression. CNS Neurosci. Ther. 2014;20:154–164. doi: 10.1111/cns.12182. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

113. Brune B., Zhou J. The role of nitric oxide (NO) in stability regulation of hypoxia inducible factor-1α (HIF-1α) Curr. Med. Chem. 2003;10:845–855. doi: 10.2174/0929867033457746. [PubMed] [CrossRef] [Google Scholar]

114. Chen Z.Y., Wang L., Asavaritkrai P., Noguchi C.T. Up-regulation of erythropoietin receptor by nitric oxide mediates hypoxia preconditioning. J. Neurosci. Res. 2010;88:3180–3188. doi: 10.1002/jnr.22473. [PubMed] [CrossRef] [Google Scholar]

115. Kasuno K., Takabuchi S., Fukuda K., Kizaka-Kondoh S., Yodoi J., Adachi T., Semenza G.L., Hirota K. Nitric Oxide Induces Hypoxia-inducible Factor 1 Activation That Is Dependent on MAPK and Phosphatidylinositol 3-Kinase Signaling. J. Biol. Chem. 2004;279:2550–2558. doi: 10.1074/jbc.M308197200. [PubMed] [CrossRef] [Google Scholar]

116. Haase V.H. The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int. 2006;69:1302–1307. doi: 10.1038/sj.ki.5000221. [PubMed] [CrossRef] [Google Scholar]

117. Hoehn T., Felderhoff-Mueser U., Maschewski K., Stadelmann C., Sifringer M., Bittigau P., Koehne P., Hoppenz M., Obladen M., Bührer C. Hyperoxia Causes Inducible Nitric Oxide Synthase-Mediated Cellular Damage to the Immature Rat Brain. Pediatr. Res. 2003;54:179–184. doi: 10.1203/01.PDR.0000075220.17631.F1. [PubMed] [CrossRef] [Google Scholar]

118. Zhilyaev S.Y., Moskvin A.N., Platonova T.F., Gutsaeva D.R., Churilina I.V., Demchenko I.T. Hyperoxic Vasoconstriction in the Brain Is Mediated by Inactivation of Nitric Oxide by Superoxide Anions. Neurosci. Behav. Physiol. 2003;33:783–787. doi: 10.1023/A:1025145331149. [PubMed] [CrossRef] [Google Scholar]

119. Rocha-Ferreira E., Rudge B., Hughes M.P., Rahim A.A., Hristova M., Robertson N.J. Immediate Remote Ischemic Postconditioning Reduces Brain Nitrotyrosine Formation in a Piglet Asphyxia Model. Oxidative Med. Cell. Longev. 2016;2016:5763743. doi: 10.1155/2016/5763743. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

120. Attaye I., Smulders Y.M., De Waard M.C., Straaten H.M.O.-V., Smit B., Van Wijhe M.H., Musters R.J., Koolwijk P., Man A.M.E.S. The effects of hyperoxia on microvascular endothelial cell proliferation and production of vaso-active substances. Intensiv. Care Med. Exp. 2017;5:22. doi: 10.1186/s40635-017-0135-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

121. Demchenko I.T., Oury T.D., Crapo J.D., Piantadosi C.A. Regulation of the Brain’s Vascular Responses to Oxygen. Circ. Res. 2002;91:1031–1037. doi: 10.1161/01.RES.0000043500.03647.81. [PubMed] [CrossRef] [Google Scholar]

122. Pham H., Vottier G., Pansiot J., Duong-Quy S., Bollen B., Dalous J., Gallego J., Mercier J.-C., Dinh-Xuan A.T., Bonnin P., et al. Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats. Exp. Neurol. 2014;252:114–123. doi: 10.1016/j.expneurol.2013.11.025. [PubMed] [CrossRef] [Google Scholar]

123. Brenner M., Stein D., Hu P., Kufera J., Wooford M., Scalea T. Association Between Early Hyperoxia and Worse Outcomes After Traumatic Brain Injury. Arch. Surg. 2012;147:1042–1046. doi: 10.1001/archsurg.2012.1560. [PubMed] [CrossRef] [Google Scholar]

124. Davis W.B., Rennard S.I., Bitterman P.B., Crystal R.G. Pulmonary oxygen toxicity: Early reversible changes in human alveolar structures induced by hyperoxia. N. Engl. J. Med. 1983;309:878–883. doi: 10.1056/NEJM198310133091502. [PubMed] [CrossRef] [Google Scholar]

125. Reynolds R.A., Amin S.N., Jonathan S.V., Tang A.R., Lan M., Wang C., Bastarache J.A., Ware L.B., Thompson R.C. Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage. Neurocritical Care. 2021;35:30–38. doi: 10.1007/s12028-020-01136-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

126. Chu D.K., Kim L.H.-Y., Young P.J., Zamiri N., Almenawer S.A., Jaeschke R., Szczeklik W., Schünemann H.J., Neary J.D., Alhazzani W. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): A systematic review and meta-analysis. Lancet. 2018;391:1693–1705. doi: 10.1016/S0140-6736(18)30479-3. [PubMed] [CrossRef] [Google Scholar]

127. Suzuki S. Oxygen administration for postoperative surgical patients: A narrative review. J. Intensive Care. 2020;8:79. doi: 10.1186/s40560-020-00498-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

128. Smit B., Smulders Y.M., van der Wouden J.C., Oudemans-van Straaten H.M., Spoelstra-de Man A.M.E. Hemodynamic effects of acute hyperoxia: Systematic review and meta-analysis. Crit. Care. 2018;22:45. doi: 10.1186/s13054-018-1968-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

129. Chatzipanteli K., Alonso O.F., Kraydieh S., Dietrich W.D. Importance of Posttraumatic Hypothermia and Hyperthermia on the Inflammatory Response after Fluid Percussion Brain Injury: Biochemical and Immunocytochemical Studies. J. Cereb. Blood Flow Metab. 2000;20:531–542. doi: 10.1097/00004647-200003000-00012. [PubMed] [CrossRef] [Google Scholar]

130. Thompson H.J., Tkacs N.C., Saatman K.E., Raghupathi R., McIntosh T.K. Hyperthermia following traumatic brain injury: A critical evaluation. Neurobiol. Dis. 2003;12:163–173. doi: 10.1016/S0969-9961(02)00030-X. [PubMed] [CrossRef] [Google Scholar]

131. Truettner J.S., Bramlett H.M., Dietrich W.D. Hyperthermia and Mild Traumatic Brain Injury: Effects on Inflammation and the Cerebral Vasculature. J. Neurotrauma. 2017;35:940–952. doi: 10.1089/neu.2017.5303. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

132. Huang T., Solano J., He D., Loutfi M., Dietrich W.D., Kuluz J.W. Traumatic Injury Activates MAP Kinases in Astrocytes: Mechanisms of Hypothermia and Hyperthermia. J. Neurotrauma. 2009;26:1535–1545. doi: 10.1089/neu.2008.0743. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

133. Kurokawa H., Ito H., Terasaki M., Matsui H. Hyperthermia enhances photodynamic therapy by regulation of HCP1 and ABCG2 expressions via high level ROS generation. Sci. Rep. 2019;9:1638. doi: 10.1038/s41598-018-38460-z. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

134. Svedung Wettervik T.M., Engquist H., Lenell S., Howells T., Hillered L., Rostami E., Lewén A., Enblad P. Systemic Hyperthermia in Traumatic Brain Injury—Relation to Intracranial Pressure Dynamics, Cerebral Energy Metabolism, and Clinical Outcome. J. Neurosurg. Anesthesiol. 2021;33:329–336. doi: 10.1097/ANA.0000000000000695. [PubMed] [CrossRef] [Google Scholar]

135. Saxton C. Effects of severe heat stress on respiration and metabolic rate in resting man. Aviat. Space Environ. Med. 1981;52:281–286. [PubMed] [Google Scholar]

136. Mickley G.A., Cobb B.L., Farrell S.T. Brain hyperthermia alters local cerebral glucose utilization: A comparison of hyperthermic agents. Int. J. Hyperth. 1997;13:99–114. doi: 10.3109/02656739709056434. [PubMed] [CrossRef] [Google Scholar]

137. Nunneley S.A., Martin C.C., Slauson J.W., Hearon C.M., Nickerson L.D.H., Mason P.A. Changes in regional cerebral metabolism during systemic hyperthermia in humans. J. Appl. Physiol. 2002;92:846–851. doi: 10.1152/japplphysiol.00072.2001. [PubMed] [CrossRef] [Google Scholar]

138. Spiotta A.M., Stiefel M.F., Heuer G.G., Bloom S., Maloney-Wilensky E., Yang W., Grady M.S., Le Roux P.D. Brain Hyperthermia After Traumatic Brain Injury Does Not Reduce Brain Oxygen. Neurosurgery. 2008;62:864–872. doi: 10.1227/01.neu.0000316900.63124.ce. [PubMed] [CrossRef] [Google Scholar]

139. Schumacker P.T., Rowland J., Saltz S., Nelson D.P., Wood L.D. Effects of hyperthermia and hypothermia on oxygen extraction by tissues during hypovolemia. J. Appl. Physiol. 1987;63:1246–1252. doi: 10.1152/jappl.1987.63.3.1246. [PubMed] [CrossRef] [Google Scholar]

140. Edvinsson L., MacKenzie E.T., McCulloch J. Cerebral Blood Flow and Metabolism. Raven Press; New York, NY, USA: 1993. [Google Scholar]

141. Crandall C.G., Gonzalez-Alonso J. Cardiovascular function in the heat-stressed human. Acta Physiol. 2010;199:407–423. doi: 10.1111/j.1748-1716.2010.02119.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

142. Gross P.M., Harper A.M., Teasdale G.M. Interaction of histamine with noradrenergic constrictory mechanisms in cat cerebral arteries and veins. Can. J. Physiol. Pharmacol. 1983;61:756–763. doi: 10.1139/y83-117. [PubMed] [CrossRef] [Google Scholar]

143. Edvinsson L. Sympathetic control of cerebral circulation. Trends Neurosci. 1982;5:425–429. doi: 10.1016/0166-2236(82)90232-6. [CrossRef] [Google Scholar]

144. Watson P., Black K.E., Clark S.C., Maughan R.J. Exercise in the heat: Effect of fluid ingestion on blood-brain barrier permeability. Med. Sci. Sport. Exerc. 2006;38:2118–2124. doi: 10.1249/01.mss.0000235356.31932.0a. [PubMed] [CrossRef] [Google Scholar]

145. Watson P., Shirreffs S.M., Maughan R.J. Blood-brain barrier integrity may be threatened by exercise in a warm environment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005;288:R1689–R1694. doi: 10.1152/ajpregu.00676.2004. [PubMed] [CrossRef] [Google Scholar]

146. Walter E.J., Hanna-Jumma S., Carraretto M., Forni L. The pathophysiological basis and consequences of fever. Crit. Care. 2016;20:200. doi: 10.1186/s13054-016-1375-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

147. Kilpatrick M.M., Lowry D.W., Firlik A.D., Yonas H., Marion D.W. Hyperthermia in the neurosurgical intensive care unit. Neurosurgery. 2000;47:850–856. doi: 10.1097/00006123-200010000-00011. [PubMed] [CrossRef] [Google Scholar]

148. Weng W.-J., Yang C., Huang X.-J., Zhang Y.-M., Liu J.-F., Yao J.-M., Zi Zhang Z., Wu X., Mei T., Zhang C., et al. Effects of brain temperature on the outcome of patients with traumatic brain injury: A prospective observational study. J. Neurotrauma. 2019;36:1168–1174. doi: 10.1089/neu.2018.5881. [PubMed] [CrossRef] [Google Scholar]

149. Holtzclaw B.J. The febrile response in critical care: State of the science. Heart Lung J. Crit. Care. 1992;21:482–501. [PubMed] [Google Scholar]

150. Bain A.R., Smith K.J., Lewis N.C., Foster G.E., Wildfong K.W., Willie C.K., Hartley G.L., Cheung S.S., Ainslie P.N. Regional changes in brain blood flow during severe passive hyperthermia: Effects of PaCO₂ and extracranial blood flow. J. Appl. Physiol. 2013;115:653–659. doi: 10.1152/japplphysiol.00394.2013. [PubMed] [CrossRef] [Google Scholar]

151. Stocchetti N., Protti A., Lattuada M., Magnoni S., Longhi L., Ghisoni L., Egidi M., Zanier E. Impact of pyrexia on neurochemistry and cerebral oxygenation after acute brain injury. J. Neurol. Neurosurg. Psychiatry. 2005;76:1135–1139. doi: 10.1136/jnnp.2004.041269. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

152. Rossi S., Zanier E.R., Mauri I., Columbo A., Stocchetti N. Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage. J. Neurol. Neurosurg. Psychiatry. 2001;71:448–454. doi: 10.1136/jnnp.71.4.448. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

153. Nyholm L., Howells T., Lewén A., Hillered L., Enblad P. The influence of hyperthermia on intracranial pressure, cerebral oximetry and cerebral metabolism in traumatic brain injury. Upsala J. Med. Sci. 2017;122:177–184. doi: 10.1080/03009734.2017.1319440. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

154. Wang H., Wang B., Normoyle K.P., Jackson K., Spitler K., Sharrock M.F., Miller C.M., Best C., Llano D., Du R. Brain temperature and its fundamental properties: A review for clinical neuroscientists. Front. Neurosci. 2014;8:307. doi: 10.3389/fnins.2014.00307. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

155. Le Roux P., Menon D.K., Citerio G., Vespa P., Bader M.K., Brophy G.M., Diringer M.N., Stocchetti N., Videtta W., Armonda R., et al. Consensus summary statement of the international multidisciplinary consensus conference on multimodality monitoring in neurocritical care. Neurocritical Care. 2014;21:1–26. doi: 10.1007/s12028-014-0041-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

156. Rass V., Huber L., Ianosi B.-A., Kofler M., Lindner A., Picetti E., Ortolano F., Beer R., Rossi S., Smielewski P., et al. The Effect of Temperature Increases on Brain Tissue Oxygen Tension in Patients with Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Substudy. Ther. Hypothermia Temp. Manag. 2020;11:122–131. doi: 10.1089/ther.2020.0027. [PubMed] [CrossRef] [Google Scholar]

157. Kil H.Y., Zhang J., Piantadosi C.A. Brain Temperature Alters Hydroxyl Radical Production during Cerebral Ischemia/Reperfusion in Rats. J. Cereb. Blood Flow Metab. 1996;16:100–106. doi: 10.1097/00004647-199601000-00012. [PubMed] [CrossRef] [Google Scholar]

158. Dempsey R.J., Combs D.J., Maley M.E., Cowen D.E., Roy M.W., Donaldson D.L. Moderate hypothermia reduces postischemic edema development and leukotriene production. Neurosurgery. 1987;21:177–181. doi: 10.1227/00006123-198708000-00007. [PubMed] [CrossRef] [Google Scholar]

159. Haba K., Ogawa N., Mizukawa K., Mori A. Time course of changes in lipid peroxidation, pre-and postsynaptic cholinergic indices, NMDA receptor binding and neuronal death in the gerbil hippocampus following transient ischemia. Brain Res. 1991;540:116–122. doi: 10.1016/0006-8993(91)90497-J. [PubMed] [CrossRef] [Google Scholar]

160. Wells C.E. The Cerebral Circulation: The Clinical Significance of Current Concepts. Arch. Neurol. 1960;3:319–331. doi: 10.1001/archneur.1960.00450030097010. [PubMed] [CrossRef] [Google Scholar]

161. Choi H.A., Badjatia N., Mayer S.A. Hypothermia for acute brain injury—mechanisms and practical aspects. Nat. Rev. Neurol. 2012;8:214–222. doi: 10.1038/nrneurol.2012.21. [PubMed] [CrossRef] [Google Scholar]

162. Dietrich W.D., Halley M., Valdes I., Busto R. Interrelationships between increased vascular permeability and acute neuronal damage following temperature-controlled brain ischemia in rats. Acta Neuropathol. 1991;81:615–625. doi: 10.1007/BF00296371. [PubMed] [CrossRef] [Google Scholar]

163. Ginsberg M.D., Sternau L.L., Globus M.Y., Dietrich W.D., Busto R. Therapeutic modulation of brain temperature: Relevance to ischemic brain injury. Cerebrovasc. Brain Metab. Rev. 1992;4:189–225. [PubMed] [Google Scholar]

164. Kramer R.S., Sanders A.P., Lesage A.M., Woodhall B., Sealy W.C. The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest. J. Thorac. Cardiovasc. Surg. 1968;56:699–709. doi: 10.1016/S0022-5223(19)42797-9. [PubMed] [CrossRef] [Google Scholar]

165. Taft W.C., Yang K., Dixon C.E., Clifton G.L., Hayes R.L. Hypothermia attenuates the loss of hippocampal microtubule-associated protein 2 (MAP2) following traumatic brain injury. J. Cereb. Blood Flow Metab. 1993;13:796–802. doi: 10.1038/jcbfm.1993.101. [PubMed] [CrossRef] [Google Scholar]

166. Dede S., Deger Y., Meral I. Effect of Short-term Hypothermia on Lipid Peroxidation and Antioxidant Enzyme Activity in Rats. J. Vet. Med. Ser. A. 2002;49:286–288. doi: 10.1046/j.1439-0442.2002.00449.x. [PubMed] [CrossRef] [Google Scholar]

167. Truettner J.S., Bramlett H.M., Dietrich W.D. Posttraumatic therapeutic hypothermia alters microglial and macrophage polarization toward a beneficial phenotype. J. Cereb. Blood Flow Metab. 2017;37:2952–2962. doi: 10.1177/0271678X16680003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

168. Erecinska M., Thoresen M., Silver I.A. Effects of Hypothermia on Energy Metabolism in Mammalian Central Nervous System. J. Cereb. Blood Flow Metab. 2003;23:513–530. doi: 10.1097/01.WCB.0000066287.21705.21. [PubMed] [CrossRef] [Google Scholar]

169. Walter B., Bauer R., Kuhnen G., Fritz H., Zwiener U. Coupling of cerebral blood flow and oxygen metabolism in infant pigs during selective brain hypothermia. J. Cereb. Blood Flow Metab. 2000;20:1215–1224. doi: 10.1097/00004647-200008000-00007. [PubMed] [CrossRef] [Google Scholar]

170. Jensen A., Garnier Y., Berger R. Dynamics of fetal circulatory responses to hypoxia and asphyxia. Eur. J. Obstet. Gynecol. Reprod. Biol. 1999;84:155–172. doi: 10.1016/S0301-2115(98)00325-X. [PubMed] [CrossRef] [Google Scholar]

171. Chihara H., Blood A.B., Hunter C.J., Power G.G. Effect of Mild Hypothermia and Hypoxia on Blood Flow and Oxygen Consumption of the Fetal Sheep Brain. Pediatr. Res. 2003;54:665–671. doi: 10.1203/01.PDR.0000084115.31416.17. [PubMed] [CrossRef] [Google Scholar]

172. Hashem M., Zhang Q., Wu Y., Johnson T.W., Dunn J.F. Using a multimodal near-infrared spectroscopy and MRI to quantify gray matter metabolic rate for oxygen: A hypothermia validation study. NeuroImage. 2020;206:116315. doi: 10.1016/j.neuroimage.2019.116315. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

173. Pichler G., Baumgartner S., Biermayr M., Dempsey E., Fuchs H., Goos T.G., Lista G., Lorenz L., Karpinski L., Mitra S., et al. Cerebral regional tissue Oxygen Saturation to Guide Oxygen Delivery in preterm neonates during immediate transition after birth (COSGOD III): An investigator-initiated, randomized, multi-center, multi-national, clinical trial on additional cerebral tissue oxygen saturation monitoring combined with defined treatment guidelines versus standard monitoring and treatment as usual in premature infants during immediate transition: Study protocol for a randomized controlled trial. Trials. 2019;20:178. doi: 10.1186/s13063-019-3258-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

174. Laurikkala J., Aneman A., Peng A., Reinikainen M., Pham P., Jakkula P., Hästbacka J., Wilkman E., Loisa P., Toppila J., et al. Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: A post-hoc analysis of the COMACARE trial. Crit. Care. 2021;25:350. doi: 10.1186/s13054-021-03764-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

175. Clifton G.L., Allen S., Barrodale P., Plenger P., Berry J., Koch S., Fletcher J., Hayes R.L., Choi S.C. A Phase II Study of Moderate Hypothermia in Severe Brain Injury. J. Neurotrauma. 1993;10:263–271. doi: 10.1089/neu.1993.10.263. [PubMed] [CrossRef] [Google Scholar]

176. Rösli D., Schnüriger B., Candinas D., Haltmeier T. The Impact of Accidental Hypothermia on Mortality in Trauma Patients Overall and Patients with Traumatic Brain Injury Specifically: A Systematic Review and Meta-Analysis. World J. Surg. 2020;44:4106–4117. doi: 10.1007/s00268-020-05750-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

177. Wu X., Tao Y., Marsons L., Dee P., Yu D., Guan Y., Zhou X. The effectiveness of early prophylactic hypothermia in adult patients with traumatic brain injury: A systematic review and meta-analysis. Aust. Crit. Care. 2021;34:83–91. doi: 10.1016/j.aucc.2020.05.005. [PubMed] [CrossRef] [Google Scholar]

178. Tokutomi T., Morimoto K., Miyagi T., Yamaguchi S., Ishikawa K., Shigemori M. Optimal Temperature For The Management Of Severe Traumatic Brain Injury: Effect Of Hypothermia On Intracranial Pressure, Systemic And Intracranial Hemodynamics, And Metabolism. Neurosurgery. 2007;61((Suppl. 1)):102–112. doi: 10.1227/01.neu.0000279221.38257.1a. [PubMed] [CrossRef] [Google Scholar]

179. Ghosh A., Highton D., Kolyva C., Tachtsidis I., Elwell C.E., Smith M. Hyperoxia results in increased aerobic metabolism following acute brain injury. J. Cereb. Blood Flow Metab. 2017;37:2910–2920. doi: 10.1177/0271678X16679171. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

180. Yang D., Ma L., Wang P., Yang D., Zhang Y., Zhao X., Lv J., Zhang J., Zhang Z., Gao F. Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke. Int. J. Mol. Med. 2019;43:1193–1202. doi: 10.3892/ijmm.2018.4037. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

181. Liang J., Qi Z., Liu W., Wang P., Shi W., Dong W., Ji X., Luo Y., Liu K.J. Normobaric Hyperoxia Slows Blood–Brain Barrier Damage and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in Cerebral Ischemia. Stroke. 2015;46:1344–1351. doi: 10.1161/STROKEAHA.114.008599. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

182. Braswell C., Crowe D.T. Hyperbaric oxygen therapy. Compend. Contin. Educ. Vet. 2012;34:E1–E6. [PubMed] [Google Scholar]

183. Sanchez E.C. Mechanisms of action of hyperbaric oxygenation in stroke: A review. Crit. Care Nurs. Q. 2013;36:290–298. doi: 10.1097/CNQ.0b013e318294e9e3. [PubMed] [CrossRef] [Google Scholar]

184. Liang F., Sun L., Yang J., Liu X.-H., Zhang J., Zhu W.-Q., Yang L., Nan D. The effect of different atmosphere absolute hyperbaric oxygen on the expression of extracellular histones after traumatic brain injury in rats. Cell Stress Chaperones. 2020;25:1013–1024. doi: 10.1007/s12192-020-01137-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

185. Xu Z., Huang Y., Mao P., Zhang J., Li Y. Sepsis and ARDS: The dark side of histones. Mediat. Inflamm. 2015;2015:205054. doi: 10.1155/2015/205054. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

186. Palzur E., Vlodavsky E., Mulla H., Arieli R., Feinsod M., Soustiel J.F. Hyperbaric oxygen therapy for reduction of secondary brain damage in head injury: An animal model of brain contusion. J. Neurotrauma. 2004;21:41–48. doi: 10.1089/089771504772695931. [PubMed] [CrossRef] [Google Scholar]

187. Palzur E., Zaaroor M., Vlodavsky E., Milman F., Soustiel J.F. Neuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane properties. Brain Res. 2008;1221:126–133. doi: 10.1016/j.brainres.2008.04.078. [PubMed] [CrossRef] [Google Scholar]

188. Rockswold G.L., Ford S.E., Anderson D.C., Bergman T.A., Sherman R.E. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J. Neurosurg. 1992;76:929–934. doi: 10.3171/jns.1992.76.6.0929. [PubMed] [CrossRef] [Google Scholar]

189. Rockswold S.B., Rockswold G.L., Zaun D.A., Liu J. A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. J. Neurosurg. 2013;118:1317–1328. doi: 10.3171/2013.2.JNS121468. [PubMed] [CrossRef] [Google Scholar]

190. Harch P.G., Andrews S.R., Rowe C.J., Lischka J.R., Townsend M.H., Yu Q., E Mercante D. Hyperbaric oxygen therapy for mild traumatic brain injury persistent postconcussion syndrome: A randomized controlled trial. Med. Gas Res. 2020;10:8–20. doi: 10.4103/2045-9912.279978. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

191. Amir H., Shai E. The Hyperoxic-Hypoxic Paradox. Biomolecules. 2020;10:958. doi: 10.3390/biom10060958. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

192. Annoni F., Peluso L., Bogossian E.G., Creteur J., Zanier E., Taccone F. Brain Protection after Anoxic Brain Injury: Is Lactate Supplementation Helpful? Cells. 2021;10:1714. doi: 10.3390/cells10071714. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

193. Phillis J.W., Song D., Guyot L.L., O’Regan M.H. Lactate reduces amino acid release and fuels recovery of function in the ischemic brain. Neurosci. Lett. 1999;272:195–198. doi: 10.1016/S0304-3940(99)00584-4. [PubMed] [CrossRef] [Google Scholar]

194. Berthet C., Lei H., Thevenet J., Gruetter R., Magistretti P.J., Hirt L. Neuroprotective role of lactate after cerebral ischemia. J. Cereb. Blood Flow Metab. 2009;29:1780–1789. doi: 10.1038/jcbfm.2009.97. [PubMed] [CrossRef] [Google Scholar]

195. Horn T., Klein J. Neuroprotective effects of lactate in brain ischemia: Dependence on anesthetic drugs. Neurochem. Int. 2013;62:251–257. doi: 10.1016/j.neuint.2012.12.017. [PubMed] [CrossRef] [Google Scholar]

196. Berthet C., Castillo X., Magistretti P.J., Hirt L. New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: Extended benefit after intracerebroventricular injection and efficacy of intravenous administration. Cerebrovasc. Dis. 2012;34:329–335. doi: 10.1159/000343657. [PubMed] [CrossRef] [Google Scholar]

197. Ichai C., Armando G., Orban J.-C., Berthier F., Rami L., Samat-Long C., Grimaud D., Leverve X. Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients. Intensiv. Care Med. 2009;35:471–479. doi: 10.1007/s00134-008-1283-5. [PubMed] [CrossRef] [Google Scholar]

198. Bouzat P., Sala N., Suys T., Zerlauth J.-B., Marques-Vidal P., Feihl F., Bloch J., Messerer M., Levivier M., Meuli R., et al. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensiv. Care Med. 2014;40:412–421. doi: 10.1007/s00134-013-3203-6. [PubMed] [CrossRef] [Google Scholar]

199. Krep H., Breil M., Sinn D., Hagendorff A., Hoeft A., Fischer M. Effects of hypertonic versus isotonic infusion therapy on regional cerebral blood flow after experimental cardiac arrest cardiopulmonary resuscitation in pigs. Resuscitation. 2004;63:73–83. doi: 10.1016/j.resuscitation.2004.03.023. [PubMed] [CrossRef] [Google Scholar]

200. Ros J., Pecinska N., Alessandri B., Landolt H., Fillenz M. Lactate reduces glutamate-induced neurotoxicity in rat cortex. J. Neurosci. Res. 2001;66:790–794. doi: 10.1002/jnr.10043. [PubMed] [CrossRef] [Google Scholar]

201. Sørensen A.T., Ledri M., Melis M., Nikitidou Ledri L., Andersson M., Kokaia M. Altered Chloride Homeo-stasis Decreases the Action Potential Threshold and Increases Hyperexcitability in Hippocampal Neu-rons. eNeuro. 2018;4 doi: 10.1523/ENEURO.0172-17.2017. [PMC free article] [PubMed] [CrossRef] [Google Scholar]