Severe traumatic brain injury: a modern understanding of the pathophysiological mechanisms of brain damage

A.V. Tsarev; V.I. Zhilyuk; A.E. Lievykh; A.V.  Bukreieva

doi:10.26641/2307-0404.2025.4.348754

Authors

A.V. Tsarev Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-2611-604X
V.I. Zhilyuk Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0003-2259-0622
A.E. Lievykh Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-0615-5092
A.V. Bukreieva Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0009-0006-5173-7055

DOI:

https://doi.org/10.26641/2307-0404.2025.4.348754

Keywords:

traumatic brain injury, cerebral metabolism, excitotoxicity, neuroinflammation, metabolic crisis, intensive care

Abstract

The review article presents modern ideas about the molecular and cellular mechanisms of brain damage in severe traumatic brain injury (TBI). The aim of the study is to analyze the pathophysiological links of primary and secondary brain damage in severe TBI in order to identify pathogenetically justified areas of intensive care. An electronic search was performed in PubMed and Google Scholar, the abstract database of scientific literature Scopus for the period 2001-2025. The search for information was carried out using the keywords: "traumatic brain injury", "cerebral metabolism", "excitotoxicity", "neuroinflammation", "metabolic crisis", "intensive care". Using bibliographic and analytical methods, 1128 sources were selected and processed, including evidence-based randomized trials, systematic reviews and others, 858 were selected and 83 of the most relevant sources were analyzed. It is fundamental to understand the fact that the pathological effect on the brain at the time of injury has not ended, but only begins, leading to secondary damage – the main point of application of the complex of intensive care for severe TBI. Since the prevention and limitation of the influence of secondary pathological factors can significantly improve the results of treatment of severe TBI. The main molecular and cellular links in the pathogenesis of severe traumatic brain injury are the development of energy deficiency, excitotoxicity with overload of nerve cells with calcium ions, hyperproduction of reactive oxygen species and nitric oxide, chronic neuroinflammation that activates microglia, which leads to the activation of signals of cellular death of nerve cells through necrosis, apoptosis and autophagy. A new concept of the development of metabolic crisis is presented, which complements our understanding of the pathophysiological mechanisms of brain damage in severe TBI. The concept of metabolic crisis, which differs from the mechanisms of ischemia, reshapes our understanding of secondary brain damage – the main point of application of the complex of intensive care for severe TBI. In which mitochondria play a central role and act as one of the main factors in determining the death or life of brain cells. Therefore, the development of neuroprotection trends for preventing and limiting the impact of secondary pathological factors can significantly improve the neurological outcomes of treatment of patients with severe TBI.

References

Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic brain injury: An overview of epidemiology, pathophysiology, and medical management. Med Clin N Am. 2020;104:213-38. doi: https://doi.org/10.1016/j.mcna.2019.11.001

Chernenko II. Peculiarities of rehabilitation of patients after combat craniocerebral trauma. Psychiatry, Neurology and Medical Psychology. 2022;20:19-24. doi: https://doi.org/10.26565/2312-5675-2022-20-03

Naumenko Y, Yuryshinetz I, Zabenko Y, Pivneva T. Mild traumatic brain injury as a pathological process. Heliyon. 2023;9:e18342. doi: https://doi.org/10.1016/j.heliyon.2023.e18342

Crupi R, Cordaro M, Cuzzocrea S, Impellizzeri D. Management of traumatic brain injury: From present to future. Antioxidants. 2020;9(4):297. doi: https://doi.org/10.3390/antiox9040297

Siwicka-Gieroba D, Robba C, Gołacki J, Badenes R, Dabrowsky W. Cerebral oxygen delivery and consumption in brain-injured patients. J Pers Med. 2022;12:1763. doi: https://doi.org/10.3390/jpm12111763

Posner JB, Saper CB, Schiff ND, Claassen J. Plum and Posner`s diagnosis of stupor and coma. Fifth edition. New York: Oxford University Press; 2019. doi: https://doi.org/10.1093/med/9780190208875.001.0001

Wijdicks EFM. The Comatose Patient. New York: Oxford University Press; 2008.

Volpi PC, Robba C, Rota M, Vargiolu А, Cite-rio 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: https://doi.org/10.1186/s12873-018-0197-y

Özugur S, Kunz L, Straka H. Relationship between oxygen consumption and neuronal activity in a defined neural circuit. BMC Biol. 2020;18:76. doi: https://doi.org/10.1186/s12915-020-00811-6

Martini RP, Deem S, Treggiari MM. Targeting brain tissue oxygenation in traumatic brain injury. Respir. Care 2012;58:162-72. doi: https://doi.org/10.4187/respcare.0194

Okonkwo DO, Shutter LA, Moore C, Temkin NR, Puccio ARN, Madden CJ, et al. Brain oxygen optimization in severe traumatic brain injury phase-II: A phase II randomized trial. Critical Care Medicine. 2017;45(11):1907-14. doi: https://doi.org/10.1097/CCM.0000000000002619

Brooks GA, Martin NA. Cerebral metabolism following traumatic brain injury: new discoveries with implications for treatment. Frontiers in Neuroscience. 2015;8:408. doi: https://doi.org/10.3389/fnins.2014.00408

Glenn TC, Kelly DF, Boscardin WJ, McArthur DL, Vespa P, Oertel M. et al. Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism. J Cereb Blood Flow Metab. 2003;23:1239-50. doi: https://doi.org/10.1097/01.WCB.0000089833.23606.7F

Xie Q, Wu HB, Yan YF, Liu M, Wang ES. 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;100:118-27. doi: https://doi.org/10.1016/j.wneu.2016.12.097

Tas J, Beqiri E, van Kaam RC, Czosnyka M, Donnelly J, Haeren RH 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: https://doi.org/10.1089/neu.2021.0197

Soustiel JF, Glenn TC, Shik V, Boscardin J, Mahamid E, Zaaroor M. Monitoring of cerebral blood flow and metabolism in traumatic brain injury. J. Neurotrauma. 2005;22:955-65. doi: https://doi.org/10.1089/neu.2005.22.95

Taylor JM, Zhu XH, Zhang Y, Chen W. Dynamic correlations between hemodynamic, metabolic, and neuro¬nal responses to acute whole-brain ischemia. NMR Biomed. 2015;28(11):1357-65. doi: https://doi.org/10.1002/nbm.3408.

Almeida A, Almeida J, Bolanos JP, Moncada S. Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Nat Acad Sci USA. 2001;98(26):15294-9. doi: https://doi.org/10.1073/pnas.0502903102

Kasischke KA, Vishwasrao HD, Fisher PJ, Zip-fel WR, Webb WW. Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science. 2004;305(5680):99-103. doi: https://doi.org/10.1126/science.1096485

Chomova M, Zitnanova I. Look into brain energy crisis and membrane pathophysiology in ischemia and reperfusion. Stress. 2016;19(4):341-8. doi: https://doi.org/10.1080/10253890.2016.1174848

Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. 2009;11:747-52.

doi: https://doi.org/ 10.1038/ncb1881

Kilbaugh TJ, Karlsson M, Byro M, Bebee A, Ralston J, Sullivan S, et al. Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain. Experimental Neurology. 2015;271:136-44. doi: https://doi.org/10.1016/j.expneurol.2015.05.009

Ying W, Chen Y, Alano CC, Swanson RA. Tricarboxylic acid cycle substrates prevent PARP-mediated death of neurons and astrocytes. J Cereb Blood Flow Metab. 2002;22(7):774-9. doi: https://doi.org/10.1097/00004647-200207000-00002

Bouzier-Sore AK, Canioni P, Merle M. Effect of exogenous lactate on rat glioma metabolism. J Neurosci Res. 2001;65(6):543-8. doi: https://doi.org/10.1002/jnr.1184.

Luan Y, Jiang L, Luan Y, Xie Y, Yang Y, Ren KD. Mitophagy and traumatic brain injury: Regu¬latory mechanisms and therapeutic potentials. Oxid Med Cell Longev. 2023;20:1649842. doi: https://doi.org/10.1155/2023/1649842

Glenn TC, Martin NA, Horning MA, McArthur DL, Hovda DA, Vespa P, et al. Lactate: brain fuel in human traumatic brain injury: a comparison with normal healthy control subjects. J Neurotrauma. 2015;32(11):820-32. doi: https://doi.org/10.1089/neu.2014.3483.

Ros J, Pecinska N, Alessandri B, Landolt H, Fillenz M. Lactate reduces glutamate-induced neurotoxicity in rat cortex. J Neurosci Res. 2001;66(5):790-4. doi: https://doi.org/10.1002/jnr.10043

Bouzat P, Sala N, Suys T, Zerlauth JB, Marques-Vidal P, Feihl F. et al. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensive Care Med. 2014;40:412-21. doi: https://doi.org/10.1007/s00134-013-3203-6

Ochiai K, Zhang J, Gong G, Zhang Y, Liu J, Ye Y, et al. Effects of augmented delivery of pyruvate on myocardial high-energy phosphate metabolism at high workstate. Am J Physiol Heart Circ Physiol. 2001;281(4):H1823-32. doi: https://doi.org/10.1152/ajpheart.2001.281.4.H1823

Cheng G, Kong RH, Zhang LM, Zhang JN. Mito-chondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. British journal of pharmacology. 2012;167(4):699-719. doi: https://doi.org/10.1111/j.1476-5381.2012.02025.x

Niyonkuru C, Wagner AK, Ozawa H, Amin K, Goyal A, Fabio A. Group-based trajectory analysis appli-cations for prognostic biomarker model development in severe TBI: A practical example. J Neurotrauma 2013;30:938-45. doi: https://doi.org/10.1089/neu.2012.2578

Guerriero RM, Giza C, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015;15:27. doi: https://doi.org/10.1007/s11910-015-0545-1

Ladak AA, Enam SA, Ibrahim MT. A review of the molecular mechanisms of traumatic brain injury. World Neurosurg. 2019;131:126-32. doi: https://doi.org/10.1016/j.wneu.2019.07.039

Wang Y, Qin ZH. Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis Int J Program Cell Death. 2010;15:1382-1402. doi: https://doi.org/10.1007/s10495-010-0481-0

Baracaldo-Santamaría D, Ariza-Salamanca DF, Corrales-Hernández MG, Pachón-Londoño MJ, Hernan-dez-Duarte I, Calderon-Ospina CA. Revisiting excito-toxicity in traumatic brain injury: From bench to bedside. Pharmaceutics. 2022;14(1):152. doi: https://doi.org/10.3390/pharmaceutics14010152

Kunz A, Dirnagl U, Mergenthaler P. Acute patho-physiological processes after ischaemic and traumatic brain injury. Best Pract Res Clin Anaesthesiol. 2010;24:495-509. doi: https://doi.org/10.1016/j.bpa.2010.10.001

Hiebert JB, Shen Q, Thimmesch AR, Pierce JD. Traumatic brain injury and mitochondrial dysfunction. Am J Med Sci. 2015;350:132-38. doi: https://doi.org/10.1097/MAJ.0000000000000506

Pandya JD, Leung LY, Flerlage WJ, Gilsdorf JS, Bryant YD Shear D. Comprehensive profile of acute mitochondrial dysfunction in a preclinical model of severe penetrating TBI. Front Neurol. 2019;10:605. doi: https://doi.org/10.1016/j.freeradbiomed.2023.02.001

Tavazzi B, Signoretti S, Lazzarino G, Amorini AM, Delfini R, Cimatti M, et al. Cerebral oxidative stress and depression of energy metabolism correlate with severity of diffuse brain injury in rats. Neurosurgery. 2005;56:582-89. doi: https://doi.org/10.1227/01.neu.0000156715.04900.

Choi K, Kim J, Kim GW, Choi C. Oxidative stress-induced necrotic cell death via mitochondira – dependent burst of reactive oxygen species. Curr Neurovasc Res. 2009;6:213-22. doi: https://doi.org/10.2174/156720209789630375.

Aranda-Rivera AK, Cruz-Gregorio A, Arancibia-Hernández YL, Hernández-Cruz EY, Pedraza-Chaverri J. RONS and oxidative stress: An overview of basic concepts. Oxygen. 2022;2:437-78. doi: https://doi.org/10.3390/oxygen2040030

Modi HR, Musyaju S, Scultetus AH, Pandya JD. Temporal changes in mitochondria-centric excitotoxic responses following severe penetrating traumatic brain injury. Biomedicines. 2025;13(7):1520. doi: https://doi.org/10.3390/biomedicines13071520

Starkov AA. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci. 2008;1147:37-52. doi: https://doi.org/10.1196/annals.1427.015

Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1-13. doi: https://doi.org/10.1042/BJ20081386.

Feissner RF, Skalska J, Gaum WE, Sheu SS. Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci. 2009;14:1197-218. doi: https://doi.org/10.2741/3303

Skulachev VP. Bioenergetic aspects of apoptosis, necrosis and mitoptosis. Apoptosis. 2006;11:473-85. doi: https://doi.org/10.1007/s10495-006-5881-9

Van Houten B, Woshner V, Santos JH. Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair (Amst). 2006;5:145-52. doi: https://doi.org/10.1016/j.dnarep.2005.03.002.

Zhang M, Teng CH, Wu FF, Ge LY, Xiao J, Zhang HY, et al. Edaravone attenuates traumatic brain injury through anti-inflammatory and anti-oxidative modulation. Experimental and therapeutic medicine. 2019;18(1):467-74. doi: https://doi.org/10.3892/etm.2019.7632.

Ismail H, Shakkour Z, Tabet M, Abdelhady S, Kobaisi A, Abedi R, et al. Traumatic brain injury: Oxi-dative stress and novel anti-oxidants such as mitoquinone and edaravone. Antioxidants. 2020;9(10):943. doi: https://doi.org/10.3390/antiox9100943.

Grüßer L, Blaumeiser-Debarry R, Krings M, Kremer B, Höllig A, Rossaint, R, Coburn M. Argon attenuates the emergence of secondary injury after traumatic brain injury within a 2-hour incubation period compared to desflurane: an in vitro study. Medical Gas Research. 2017;7(2):93-100.

doi: https://doi.org/10.4103/2045-9912.208512.

Gardner AJ, Menon DK. Moving to human trials for argon neuroprotection in neurological injury: a narrative review. British journal of anaesthesia. 2018;120(3):453-68. doi: https://doi.org/10.1016/j.bja.2017.10.017

Merigoa G, Florioc G,∙Madottob F, Maglioccac A, Silvestric I, Fumagalli F, et al. Treatment with inhaled argon: a systematic review of pre-clinical and clinical studies with meta-analysis on neuroprotective effect. eBioMedicine. 2024;103:105143. doi: https://doi.org/10.1016/j.ebiom.2024.105143.

Chiu CC, Liao YE, Yang LY, Wang JY, Tweedie D, Karnati HK, et al. Neuroinflammation in animal models of traumatic brain injury. Journal of neuroscience methods. 2016;272:38-49. doi: https://doi.org/10.1016/j.jneumeth.2016.06.018

Liu YW, Li S, Dai SS. Neutrophils in traumatic brain injury (TBI): friend or foe? J Neuroinflammation. 2018;15:146.

doi: https://doi.org/10.1186/s12974-018-1173-x

Shi K, Zhang J, Dong Jf. Dissemination of brain inflammation in traumatic brain injury. Cell Mol Immunol. 2019;16:523-30.

doi: https://doi.org/10.1038/s41423-019-0213-5

Szmydynger-Chodobska J, Strazielle N, Gandy JR, et al. Posttraumatic invasion of monocytes across the blood-cerebrospinal fluid barrier. Journal of Cerebral Blood Flow & Metabolism. 2011;32(1):93-104. doi: https://doi.org/10.1038/jcbfm.2011.111

Mira RG, Lira M, Cerpa W. Traumatic brain injury: Mechanisms of glial response. Front Physiol. 2021;12:740939. https://doi.org/10.3389/fphys.2021.740939

Corps KN, Roth TL, McGavern DB. Inflammation and Neuroprotection in Traumatic Brain Injury. JAMA Neurol. 2015;72(3):355-62. doi: https://doi.org/10.1001/jamaneurol.2014.3558

Buffo A, Rolando C, Ceruti S. Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochemical pharmacology. 2010;79:77-89.

doi: https://doi.org/ 10.1016/j.bcp.2009.09.014

Izzy S, Liu Q, Fang Z, Lule S, Wu L, Chung JY, et al. Time-dependent changes in microglia transcriptional networks following traumatic brain injury. Front Cell Neu-rosci. 2019;13:307. https://doi.org/10.3389/fncel.2019.00307

Kumar A, Alvarez-Croda DM, Stoica BA, Faden AI, Loane DJ. Microglial macrophage polarization dynamics following traumatic brain injury. J Neurotrauma. 2016;33:19. doi: https://doi.org/10.1089/neu.2015.4268

Dinet V, Petry KG, Badaut J. Brainimmune interactions and neuroinflammation after traumatic brain injury. Front Neurosci. 2019;13:1178. doi: https://doi.org/10.3389/fnins.2019.01178

Witcher KG, Bray CE, Dziabis JE, McKim DB, Benner BN, Rowe RK, et al. Traumatic brain injury-induced neuronal damage in the somatosensory cortex causes formation of rod-shaped microglia that promote astrogliosis and persistent neuroinflammation. Glia. 2018;66:2719-36. doi: https://doi.org/10.1002/glia.23523

Myer DJ, Gurkoff GG, Lee SM, Hovda DA, Sofroniew MV. Essential protective roles of reactive astro-cytes in traumatic brain injury. Brain. 2006;129(Pt 10):2761-72.

doi: https://doi.org/10.1093/brain/awl165.

Karve IP, Taylor JM, Crack PJ. The contribution of astrocytes and microglia to traumatic brain injury. British journal of pharmacology. 2016;173:692-702. doi: https://doi.org/10.1111/bph.13125

Postolache TT, Wadhawan A, Can A, Lowry CA, Woodbury M, Makkar H, et al. Inflammation in traumatic brain injury. J Alheimers Dis. 2020;74:1-28. doi: https://doi.org/10.3233/JAD-191150

Bylicky MA, Mueller GP, Day RM. Mechanisms of endogenous neuroprotective effects of astrocytes in brain injury. Oxid Med Cell Longev. 2018;2018:6501031. doi: https://doi.org/10.1155/2018/6501031

Sajja VSS, Hlavac N, Vande Vord PJ. Role of glia in memory deficits following traumatic brain injury: biomarkers of glia dysfunction. Front Integr Neurosci. 2016;10:7. doi: https://doi.org/10.3389/fnint.2016.00007

Gardner RC, Burke JF, Nettiksimmons J, Gold-man S, Tanner CM, Yaffe K. Traumatic brain injury in later life increases risk for Parkinson disease. Ann Neurol. 2015;77(6):987-95. doi: https://doi.org/10.1002/ana.24396

Dexi B, Boying G, Yanan S, Zhibo D, Shichun Y, Ligang W. Traumatic brain injury and neurodegenerative diseases: the role of axonal injury and amyloid-β. Brain Research. 2025;1865:149873. doi: https://doi.org/10.1016/j.brainres.2025.149873

Faden AI, Loane DJ. Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Neurotherapeutics. 2015;12(1):143-50. doi: https://doi.org/10.1007/s13311-014-0319-5.

González-Reyes RE, Nava-Mesa M.O, Vargas-Sán¬chez K, Ariza-Salamanca D, Mora-Muñoz L. Involvement of astrocytes in Alzheimer’s disease from a neuro¬inflammatory and oxidative stress perspective. Front Mol Neurosci 2017;10:427. doi: https://doi.org/10.3389/fnmol.2017.00427

Thapak P, Gomez-Pinilla F. The bioenergetics of traumatic brain injury and its long-term impact for brain plasticity and function. Pharmacol Res. 2024;208:107389. doi: https://doi.org/10.1016/j.phrs.2024.107389

Vespa P, Bergsneider M, Hattori N, Wu HM, Huang SC, Martin NA, et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 2005;25(6):763-74. doi: https://doi.org/10.1038/sj.jcbfm.9600073

Verweij BH, Amelink GJ, Muizelaar JP. Current concepts of cerebral oxygen transport and energy meta-bolism after severe traumatic brain injury. Prog Brain Res. 2007;161:111-24.

doi: https://doi.org/10.1016/S0079-6123(06)61008-X

Carre E, Ogier M, Boret H, Montcriol A, Bourdon L, Jean-Jacques R. Metabolic crisis in severely head-injured patients: is ischemia just the tip of the iceberg? Front Neurol. 2013;4:146. doi: https://doi.org/10.3389/fneur.2013.00146

Marcoux J, Mcarthur DA, Miller C, Glenn TC, Villablanca P, Martin NA, et al. Persistent metabolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts chronic frontal lobe brain atrophy after traumatic brain injury. Crit Care Med. 2008;36:2871-7. doi: https://doi.org/10.1097/CCM.0b013e318186a4a0

Hillered L, Enblad P. Nonischemic energy meta-bolic crisis in acute brain injury. Crit Care Med. 2008;36:2952-3. doi: https://doi.org/10.1097/CCM.0b013e3181872178

Nielsen TH, Olsen NV, Toft P, Nordström CH. Cerebral energy metabolism during mitochondrial dys-function induced by cyanide in piglets. Acta Ana¬esthesiol Scand. 2013;57(6):793-801. doi: https://doi.org/10.1111/aas.12092

Vespa P, Tubi M, Claassen J, Buitrago-Blanco M, McArthur D, Velazquez AG, et al. Metabolic crisis occurs with seizures and periodic discharges after brain trauma. Annals of Neurology. 2016;79(4):579-90. doi: https://doi.org/10.1002/ana.24606.

Xu Y, Mcarthur DL, Alger JR, Etchepare M, Hovda DA, Glenn TC, et al. Early nonischemic oxidative metabolic dysfunction leads to chronic brain atrophy in traumatic brain injury. J Cereb Blood Flow Metab. 2010;30:883-94. doi: https://doi.org/10.1038/jcbfm.2009.263

Lund A, Madsen AF, Capion T, Jensen HR, Fors-se A, Hauerberg J, et al. Brain hypoxia and metabolic crisis are common in patients with acute brain injury despite a normal intracranial pressure. Sci Rep. 2024;14:23828. doi: https://doi.org/10.1038/s41598-024-75129-2

Stein NR, Mcarthur DL, Etchepare M, Vespa PM. Early cerebral metabolic crisis after TBI influences outcome despite adequate hemodynamic resuscitation. Neurocrit Care. 2012;17:49-57. doi: https://doi.org/10.1007/s12028-012-9708-y