Post-Traumatic Cerebral Edema: Pathophysiology, Key Contributors, and Contemporary Management

Main Article Content

Nicholas Caffes, Dr. Jesse A. Stokum, Dr. Richard Zhao, PhD Ruchira M. Jha, Dr. J. Marc Simard


The development of cerebral edema following traumatic brain injury is one of the most significant predictors of outcome and is associated with high rates of morbidity and mortality. A prominent focus of neurosurgical and neurocritical care is the evaluation and aggressive management of cerebral edema and subsequent intracranial hypertension. Despite numerous advances and capabilities in neurocritical care, treatments remain primarily reactive and are instituted only after secondary pathophysiological pathways have culminated in an intracranial pressure crisis. Recent reviews have focused on several key molecular contributors to post-traumatic cerebral edema and on several potential anti-edema therapeutic targets. The present article provides a contemporary overview of post-traumatic cerebral edema by reviewing important historical concepts, fundamental pathophysiological mechanisms, various causes and key contributors specific to traumatic brain injury, and established treatments of downstream intracranial hypertension.

Article Details

How to Cite
CAFFES, Nicholas et al. Post-Traumatic Cerebral Edema: Pathophysiology, Key Contributors, and Contemporary Management. Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 19 june 2024. doi:
Review Articles


1. Maas AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. Dec 2017;16(12):987-1048. doi:10.1016/S1474-4422(17)30371-X
2. Winkler EA, Minter D, Yue JK, Manley GT. Cerebral Edema in Traumatic Brain Injury: Pathophysiology and Prospective Therapeutic Targets. Neurosurg Clin N Am. Oct 2016;27(4):473-88. doi:10.1016/
3. Donkin JJ, Vink R. Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments. Curr Opin Neurol. Jun 2010;23(3):293-9. doi:10.1097/WCO.0b013e328337f451
4. Menon DK, Ercole A. Critical care management of traumatic brain injury. Handb Clin Neurol. 2017;140:239-274. doi:10.1016/B978-0-444-63600-3.00014-3
5. Meyfroidt G, Bouzat P, Casaer MP, et al. Management of moderate to severe traumatic brain injury: an update for the intensivist. Intensive Care Med. Jun 2022;48(6):649-666. doi:10.1007/s00134-022-06702-4
6. Stocchetti N, Carbonara M, Citerio G, et al. Severe traumatic brain injury: targeted management in the intensive care unit. Lancet Neurol. Jun 2017;16(6):452-464. doi:10.1016/S1474-4422(17)30118-7
7. Jha RM, Kochanek PM, Simard JM. Pathophysiology and treatment of cerebral edema in traumatic brain injury. Neuropharmacology. Feb 2019;145(Pt B):230-246. doi:10.1016/j.neuropharm.2018.08.004
8. GF R. Acute injuries of the head. Their diagnosis, treatment, complications and sequels. Edinburgh: E & S Livingstone LTD. 1945;2nd edition
9. Weed LHM MP. Experimental alteration of brain bulk. Am J Physiol 1919;48(4):531-58.
10. Wise BL, Chater N. The value of hypertonic mannitol solution in decreasing brain mass and lowering cerebro-spinal-fluid pressure. J Neurosurg. Dec 1962;19:1038-43. doi:10.3171/jns.1962.19.12.1038
11. Klatzo I. Presidental address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol. Jan 1967;26(1):1-14. doi:10.1097/00005072-196701000-00001
12. Jha RM, Kochanek PM. Adding insight to injury: a new era in neurotrauma. Lancet Neurol. Aug 2017;16(8):578-580. doi:10.1016/S1474-4422(17)30225-9
13. Stocchetti N, Zanaboni C, Colombo A, et al. Refractory intracranial hypertension and "second-tier" therapies in traumatic brain injury. Intensive Care Med. Mar 2008;34(3):461-7. doi:10.1007/s00134-007-0948-9
14. Helgason CM. Commentary on the significance for modern neurology of the 17th century B.C. Surgical Papyrus. Can J Neurol Sci. Nov 1987;14(4):560-3.
15. Jha RM, Kochanek PM. A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis? Curr Neurol Neurosci Rep. Nov 7 2018;18(12):105. doi:10.1007/s11910-018-0912-9
16. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. Feb 1993;34(2):216-22. doi:10.1097/00005373-199302000-00006
17. Eisenberg HM, Gary HE, Jr., Aldrich EF, et al. Initial CT findings in 753 patients with severe head injury. A report from the NIH Traumatic Coma Data Bank. J Neurosurg. Nov 1990;73(5):688-98. doi:10.3171/jns.1990.73.5.0688
18. Hudak AM, Peng L, Marquez de la Plata C, et al. Cytotoxic and vasogenic cerebral oedema in traumatic brain injury: assessment with FLAIR and DWI imaging. Brain Inj. 2014;28(12):1602-9. doi:10.3109/02699052.2014.936039
19. Iaccarino C, Schiavi P, Picetti E, et al. Patients with brain contusions: predictors of outcome and relationship between radiological and clinical evolution. J Neurosurg. Apr 2014;120(4):908-18. doi:10.3171/2013.12.JNS131090
20. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in severe head injuries. Part I: the significance of intracranial pressure monitoring. J Neurosurg. Jan 1979;50(1):20-5. doi:10.3171/jns.1979.50.1.0020
21. Tucker B, Aston J, Dines M, et al. Early Brain Edema is a Predictor of In-Hospital Mortality in Traumatic Brain Injury. J Emerg Med. Jul 2017;53(1):18-29. doi:10.1016/j.jemermed.2017.02.010
22. Narayan RK, Kishore PR, Becker DP, et al. Intracranial pressure: to monitor or not to monitor? A review of our experience with severe head injury. J Neurosurg. May 1982;56(5):650-9. doi:10.3171/jns.1982.56.5.0650
23. Vik A, Nag T, Fredriksli OA, et al. Relationship of "dose" of intracranial hypertension to outcome in severe traumatic brain injury. J Neurosurg. Oct 2008;109(4):678-84. doi:10.3171/JNS/2008/109/10/0678
24. Carney N, Totten AM, O'Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. Jan 1 2017;80(1):6-15. doi:10.1227/NEU.0000000000001432
25. Andrews PJ, Harris BA, Murray GD. Hypothermia for Intracranial Hypertension after Traumatic Brain Injury. N Engl J Med. Apr 7 2016;374(14):1385. doi:10.1056/NEJMc1600339
26. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. Apr 21 2011;364(16):1493-502. doi:10.1056/NEJMoa1102077
27. Gottlieb M, Bailitz J. Does Mannitol Reduce Mortality From Traumatic Brain Injury? Ann Emerg Med. Jan 2016;67(1):83-5. doi:10.1016/j.annemergmed.2015.06.027
28. Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. N Engl J Med. Sep 22 2016;375(12):1119-30. doi:10.1056/NEJMoa1605215
29. Jha RM, Elmer J, Zusman BE, et al. Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes. Crit Care Med. Nov 2018;46(11):1792-1802. doi:10.1097/CCM.0000000000003361
30. Katayama Y, Kawamata T. Edema fluid accumulation within necrotic brain tissue as a cause of the mass effect of cerebral contusion in head trauma patients. Acta Neurochir Suppl. 2003;86:323-7. doi:10.1007/978-3-7091-0651-8_69
31. Katayama Y, Mori T, Maeda T, Kawamata T. Pathogenesis of the mass effect of cerebral contusions: rapid increase in osmolality within the contusion necrosis. Acta Neurochir Suppl. 1998;71:289-92. doi:10.1007/978-3-7091-6475-4_84
32. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. Mar 2016;36(3):513-38. doi:10.1177/0271678X15617172
33. Stokum JA, Kurland DB, Gerzanich V, Simard JM. Mechanisms of astrocyte-mediated cerebral edema. Neurochem Res. Feb 2015;40(2):317-28. doi:10.1007/s11064-014-1374-3
34. Lo WD, Betz AL, Schielke GP, Hoff JT. Transport of sodium from blood to brain in ischemic brain edema. Stroke. Jan-Feb 1987;18(1):150-7. doi:10.1161/01.str.18.1.150
35. Gerzanich V, Woo SK, Vennekens R, et al. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat Med. Feb 2009;15(2):185-91. doi:10.1038/nm.1899
36. Gido G, Kristian T, Siesjo BK. Extracellular potassium in a neocortical core area after transient focal ischemia. Stroke. Jan 1997;28(1):206-10. doi:10.1161/01.str.28.1.206
37. Wahl F, Obrenovitch TP, Hardy AM, Plotkine M, Boulu R, Symon L. Extracellular glutamate during focal cerebral ischaemia in rats: time course and calcium dependency. J Neurochem. Sep 1994;63(3):1003-11. doi:10.1046/j.1471-4159.1994.63031003.x
38. Hansson E, Muyderman H, Leonova J, et al. Astroglia and glutamate in physiology and pathology: aspects on glutamate transport, glutamate-induced cell swelling and gap-junction communication. Neurochem Int. Aug-Sep 2000;37(2-3):317-29. doi:10.1016/s0197-0186(00)00033-4
39. Lu KT, Cheng NC, Wu CY, Yang YL. NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade. Crit Care Med. Mar 2008;36(3):917-22. doi:10.1097/CCM.0B013E31816590C4
40. Su G, Kintner DB, Flagella M, Shull GE, Sun D. Astrocytes from Na(+)-K(+)-Cl(-) cotransporter-null mice exhibit absence of swelling and decrease in EAA release. Am J Physiol Cell Physiol. May 2002;282(5):C1147-60. doi:10.1152/ajpcell.00538.2001
41. Bevensee MO, Weed RA, Boron WF. Intracellular pH regulation in cultured astrocytes from rat hippocampus. I. Role Of HCO3. J Gen Physiol. Oct 1997;110(4):453-65. doi:10.1085/jgp.110.4.453
42. Kitayama J, Kitazono T, Yao H, et al. Inhibition of Na+/H+ exchanger reduces infarct volume of focal cerebral ischemia in rats. Brain Res. Dec 20 2001;922(2):223-8. doi:10.1016/s0006-8993(01)03175-4
43. Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci. Sep 17 2003;23(24):8568-77.
44. Chen M, Simard JM. Cell swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J Neurosci. Sep 1 2001;21(17):6512-21.
45. Stokum JA, Kwon MS, Woo SK, et al. SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. Glia. Jan 2018;66(1):108-125. doi:10.1002/glia.23231
46. Woo SK, Kwon MS, Geng Z, et al. Sequential activation of hypoxia-inducible factor 1 and specificity protein 1 is required for hypoxia-induced transcriptional stimulation of Abcc8. J Cereb Blood Flow Metab. Mar 2012;32(3):525-36. doi:10.1038/jcbfm.2011.159
47. O'Donnell ME, Chen YJ, Lam TI, Taylor KC, Walton JH, Anderson SE. Intravenous HOE-642 reduces brain edema and Na uptake in the rat permanent middle cerebral artery occlusion model of stroke: evidence for participation of the blood-brain barrier Na/H exchanger. J Cereb Blood Flow Metab. Feb 2013;33(2):225-34. doi:10.1038/jcbfm.2012.160
48. O'Donnell ME, Tran L, Lam TI, Liu XB, Anderson SE. Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. J Cereb Blood Flow Metab. Sep 2004;24(9):1046-56. doi:10.1097/01.WCB.0000130867.32663.90
49. Alluri H, Wilson RL, Anasooya Shaji C, et al. Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition. PLoS One. 2016;11(5):e0154427. doi:10.1371/journal.pone.0154427
50. Guilfoyle MR, Carpenter KL, Helmy A, Pickard JD, Menon DK, Hutchinson PJ. Matrix Metalloproteinase Expression in Contusional Traumatic Brain Injury: A Paired Microdialysis Study. J Neurotrauma. Oct 15 2015;32(20):1553-9. doi:10.1089/neu.2014.3764
51. Hadass O, Tomlinson BN, Gooyit M, et al. Selective inhibition of matrix metalloproteinase-9 attenuates secondary damage resulting from severe traumatic brain injury. PLoS One. 2013;8(10):e76904. doi:10.1371/journal.pone.0076904
52. Bolton SJ, Anthony DC, Perry VH. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience. Oct 1998;86(4):1245-57. doi:10.1016/s0306-4522(98)00058-x
53. Walker K, Perkins M, Dray A. Kinins and kinin receptors in the nervous system. Neurochem Int. Jan 1995;26(1):1-16; discussion 17-26. doi:10.1016/0197-0186(94)00114-a
54. Chodobski A, Zink BJ, Szmydynger-Chodobska J. Blood-brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res. Dec 2011;2(4):492-516. doi:10.1007/s12975-011-0125-x
55. Marmarou A, Takagi H, Shulman K. Biomechanics of brain edema and effects on local cerebral blood flow. Adv Neurol. 1980;28:345-58.
56. Barzo P, Marmarou A, Fatouros P, Hayasaki K, Corwin F. Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging. J Neurosurg. Dec 1997;87(6):900-7. doi:10.3171/jns.1997.87.6.0900
57. Readnower RD, Chavko M, Adeeb S, et al. Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury. J Neurosci Res. Dec 2010;88(16):3530-9. doi:10.1002/jnr.22510
58. Tanno H, Nockels RP, Pitts LH, Noble LJ. Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. Part 1: Distribution and time course of protein extravasation. J Neurotrauma. Spring 1992;9(1):21-32. doi:10.1089/neu.1992.9.21
59. Marmarou A. A review of progress in understanding the pathophysiology and treatment of brain edema. Neurosurg Focus. May 15 2007;22(5):E1. doi:10.3171/foc.2007.22.5.2
60. Simard JM, Chen M, Tarasov KV, et al. Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med. Apr 2006;12(4):433-40. doi:10.1038/nm1390
61. Graham DI, Ford I, Adams JH, et al. Ischaemic brain damage is still common in fatal non-missile head injury. J Neurol Neurosurg Psychiatry. Mar 1989;52(3):346-50. doi:10.1136/jnnp.52.3.346
62. Launey Y, Fryer TD, Hong YT, et al. Spatial and Temporal Pattern of Ischemia and Abnormal Vascular Function Following Traumatic Brain Injury. JAMA Neurol. Mar 1 2020;77(3):339-349. doi:10.1001/jamaneurol.2019.3854
63. Bouma GJ, Muizelaar JP, Stringer WA, Choi SC, Fatouros P, Young HF. Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg. Sep 1992;77(3):360-8. doi:10.3171/jns.1992.77.3.0360
64. Diringer MN, Videen TO, Yundt K, et al. Regional cerebrovascular and metabolic effects of hyperventilation after severe traumatic brain injury. J Neurosurg. Jan 2002;96(1):103-8. doi:10.3171/jns.2002.96.1.0103
65. Stokum JA, Cannarsa GJ, Wessell AP, Shea P, Wenger N, Simard JM. When the Blood Hits Your Brain: The Neurotoxicity of Extravasated Blood. Int J Mol Sci. May 12 2021;22(10)doi:10.3390/ijms22105132
66. Wagner KR, Xi G, Hua Y, et al. Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke. Mar 1996;27(3):490-7. doi:10.1161/01.str.27.3.490
67. Xi G, Keep RF, Hoff JT. Pathophysiology of brain edema formation. Neurosurg Clin N Am. Jul 2002;13(3):371-83. doi:10.1016/s1042-3680(02)00007-4
68. Urday S, Kimberly WT, Beslow LA, et al. Targeting secondary injury in intracerebral haemorrhage--perihaematomal oedema. Nat Rev Neurol. Feb 2015;11(2):111-22. doi:10.1038/nrneurol.2014.264
69. Garrett MC, Otten ML, Starke RM, et al. Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res. Nov 17 2009;1298:171-7. doi:10.1016/j.brainres.2009.04.047
70. Aslam M, Ahmad N, Srivastava R, Hemmer B. TNF-alpha induced NFkappaB signaling and p65 (RelA) overexpression repress Cldn5 promoter in mouse brain endothelial cells. Cytokine. Feb 2012;57(2):269-75. doi:10.1016/j.cyto.2011.10.016
71. Xi G, Keep RF, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg. Dec 1998;89(6):991-6. doi:10.3171/jns.1998.89.6.0991
72. Katayama Y, Tsubokawa T, Kinoshita K, Himi K. Intraparenchymal blood-fluid levels in traumatic intracerebral haematomas. Neuroradiology. 1992;34(5):381-3. doi:10.1007/BF00596494
73. Katayama Y, Tsubokawa T, Miyazaki S, Kawamata T, Yoshino A. Oedema fluid formation within contused brain tissue as a cause of medically uncontrollable elevation of intracranial pressure: the role of surgical therapy. Acta Neurochir Suppl (Wien). 1990;51:308-10. doi:10.1007/978-3-7091-9115-6_104
74. Kawamata T, Katayama Y, Aoyama N, Mori T. Heterogeneous mechanisms of early edema formation in cerebral contusion: diffusion MRI and ADC mapping study. Acta Neurochir Suppl. 2000;76:9-12. doi:10.1007/978-3-7091-6346-7_2
75. Kushi H, Katayama Y, Shibuya T, Tsubokawa T, Kuroha T. Gadolinium DTPA-enhanced magnetic resonance imaging of cerebral contusions. Acta Neurochir Suppl (Wien). 1994;60:472-4. doi:10.1007/978-3-7091-9334-1_129
76. Kawamata T, Mori T, Sato S, Katayama Y. Tissue hyperosmolality and brain edema in cerebral contusion. Neurosurg Focus. May 15 2007;22(5):E5. doi:10.3171/foc.2007.22.5.6
77. Cunningham AS, Salvador R, Coles JP, et al. Physiological thresholds for irreversible tissue damage in contusional regions following traumatic brain injury. Brain. Aug 2005;128(Pt 8):1931-42. doi:10.1093/brain/awh536
78. Von Oettingen G, Bergholt B, Gyldensted C, Astrup J. Blood flow and ischemia within traumatic cerebral contusions. Neurosurgery. Apr 2002;50(4):781-8; discussion 788-90. doi:10.1097/00006123-200204000-00019
79. Obrist WD, Langfitt TW, Jaggi JL, Cruz J, Gennarelli TA. Cerebral blood flow and metabolism in comatose patients with acute head injury. Relationship to intracranial hypertension. J Neurosurg. Aug 1984;61(2):241-53. doi:10.3171/jns.1984.61.2.0241
80. Coles JP, Fryer TD, Smielewski P, et al. Defining ischemic burden after traumatic brain injury using 15O PET imaging of cerebral physiology. J Cereb Blood Flow Metab. Feb 2004;24(2):191-201. doi:10.1097/01.WCB.0000100045.07481.DE
81. Wu HM, Huang SC, Vespa P, Hovda DA, Bergsneider M. Redefining the peri-contusional penumbra following traumatic brain injury: evidence of deteriorating metabolic derangements based on positron emission tomography. J Neurotrauma. Mar 1 2013;30(5):352-60. doi:10.1089/neu.2012.2610
82. Zwienenberg M, Muizelaar JP. Severe pediatric head injury: the role of hyperemia revisited. J Neurotrauma. Oct 1999;16(10):937-43. doi:10.1089/neu.1999.16.937
83. Evans JP, Scheinker IM. Histologic studies of the brain following head trauma; post-traumatic petechial and massive intracerebral hemorrhage. J Neurosurg. Mar 1946;3:101-13. doi:10.3171/jns.1946.3.2.0101
84. Langfitt TW, Tannanbaum HM, Kassell NF. The etiology of acute brain swelling following experimental head injury. J Neurosurg. Jan 1966;24(1):47-56. doi:10.3171/jns.1966.24.1.0047
85. Bruce DA, Alavi A, Bilaniuk L, Dolinskas C, Obrist W, Uzzell B. Diffuse cerebral swelling following head injuries in children: the syndrome of "malignant brain edema". J Neurosurg. Feb 1981;54(2):170-8. doi:10.3171/jns.1981.54.2.0170
86. Fieschi C, Battistini N, Beduschi A, Boselli L, Rossanda M. Regional cerebral blood flow and intraventricular pressure in acute head injuries. J Neurol Neurosurg Psychiatry. Dec 1974;37(12):1378-88. doi:10.1136/jnnp.37.12.1378
87. Jaggi JL, Obrist WD, Gennarelli TA, Langfitt TW. Relationship of early cerebral blood flow and metabolism to outcome in acute head injury. J Neurosurg. Feb 1990;72(2):176-82. doi:10.3171/jns.1990.72.2.0176
88. Muizelaar JP, Ward JD, Marmarou A, Newlon PG, Wachi A. Cerebral blood flow and metabolism in severely head-injured children. Part 2: Autoregulation. J Neurosurg. Jul 1989;71(1):72-6. doi:10.3171/jns.1989.71.1.0072
89. Bouma GJ, Muizelaar JP, Bandoh K, Marmarou A. Blood pressure and intracranial pressure-volume dynamics in severe head injury: relationship with cerebral blood flow. J Neurosurg. Jul 1992;77(1):15-9. doi:10.3171/jns.1992.77.1.0015
90. Sakas DE, Bullock MR, Patterson J, Hadley D, Wyper DJ, Teasdale GM. Focal cerebral hyperemia after focal head injury in humans: a benign phenomenon? J Neurosurg. Aug 1995;83(2):277-84. doi:10.3171/jns.1995.83.2.0277
91. Holland MC, Mackersie RC, Morabito D, et al. The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. J Trauma. Jul 2003;55(1):106-11. doi:10.1097/01.TA.0000071620.27375.BE
92. Salim A, Hadjizacharia P, Dubose J, et al. Persistent hyperglycemia in severe traumatic brain injury: an independent predictor of outcome. Am Surg. Jan 2009;75(1):25-9.
93. Shi J, Dong B, Mao Y, et al. Review: Traumatic brain injury and hyperglycemia, a potentially modifiable risk factor. Oncotarget. Oct 25 2016;7(43):71052-71061. doi:10.18632/oncotarget.11958
94. Alarcon JD, Rubiano AM, Okonkwo DO, et al. Elevation of the head during intensive care management in people with severe traumatic brain injury. Cochrane Database Syst Rev. Dec 28 2017;12:CD009986. doi:10.1002/14651858.CD009986.pub2
95. Meixensberger J, Baunach S, Amschler J, Dings J, Roosen K. Influence of body position on tissue-pO2, cerebral perfusion pressure and intracranial pressure in patients with acute brain injury. Neurol Res. Jun 1997;19(3):249-53. doi:10.1080/01616412.1997.11740808
96. Schneider GH, von Helden GH, Franke R, Lanksch WR, Unterberg A. Influence of body position on jugular venous oxygen saturation, intracranial pressure and cerebral perfusion pressure. Acta Neurochir Suppl (Wien). 1993;59:107-12. doi:10.1007/978-3-7091-9302-0_19
97. Rosner MJ, Coley IB. Cerebral perfusion pressure, intracranial pressure, and head elevation. J Neurosurg. Nov 1986;65(5):636-41. doi:10.3171/jns.1986.65.5.0636
98. James HE, Langfitt TW, Kumar VS, Ghostine SY. Treatment of intracranial hypertension. Analysis of 105 consecutive, continuous recordings of intracranial pressure. Acta Neurochir (Wien). 1977;36(3-4):189-200. doi:10.1007/BF01405391
99. Huang SJ, Chang L, Han YY, Lee YC, Tu YK. Efficacy and safety of hypertonic saline solutions in the treatment of severe head injury. Surg Neurol. Jun 2006;65(6):539-46; discussion 546. doi:10.1016/j.surneu.2005.11.019
100. Schwimmbeck F, Voellger B, Chappell D, Eberhart L. Hypertonic Saline Versus Mannitol for Traumatic Brain Injury: A Systematic Review and Meta-analysis With Trial Sequential Analysis. J Neurosurg Anesthesiol. Jan 2021;33(1):10-20. doi:10.1097/ANA.0000000000000644
101. Bugedo G, Santis C. Intracranial hypertension and deep sedation. Crit Care. Nov 4 2019;23(1):342. doi:10.1186/s13054-019-2578-3
102. McCall M, Jeejeebhoy K, Pencharz P, Moulton R. Effect of neuromuscular blockade on energy expenditure in patients with severe head injury. JPEN J Parenter Enteral Nutr. Jan-Feb 2003;27(1):27-35. doi:10.1177/014860710302700127
103. Sanfilippo F, Santonocito C, Veenith T, Astuto M, Maybauer MO. The role of neuromuscular blockade in patients with traumatic brain injury: a systematic review. Neurocrit Care. Apr 2015;22(2):325-34. doi:10.1007/s12028-014-0061-1
104. Wang X, Ding X, Tong Y, et al. Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials. J Anesth. Dec 2014;28(6):821-7. doi:10.1007/s00540-014-1845-3
105. Battaglini D, Anania P, Rocco PRM, et al. Escalate and De-Escalate Therapies for Intracranial Pressure Control in Traumatic Brain Injury. Front Neurol. 2020;11:564751. doi:10.3389/fneur.2020.564751
106. Crossley S, Reid J, McLatchie R, et al. A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury. Crit Care. Apr 17 2014;18(2):R75. doi:10.1186/cc13835
107. Lewis SR, Evans DJ, Butler AR, Schofield-Robinson OJ, Alderson P. Hypothermia for traumatic brain injury. Cochrane Database Syst Rev. Sep 21 2017;9:CD001048. doi:10.1002/14651858.CD001048.pub5
108. Honeybul S, Ho KM, Lind CR. What can be learned from the DECRA study. World Neurosurg. Jan 2013;79(1):159-61. doi:10.1016/j.wneu.2012.08.012
109. Shutter LA, Timmons SD. Intracranial Pressure Rescued by Decompressive Surgery after Traumatic Brain Injury. N Engl J Med. Sep 22 2016;375(12):1183-4. doi:10.1056/NEJMe1609722
110. Stokum JA, Gerzanich V, Sheth KN, Kimberly WT, Simard JM. Emerging Pharmacological Treatments for Cerebral Edema: Evidence from Clinical Studies. Annu Rev Pharmacol Toxicol. Jan 6 2020;60:291-309. doi:10.1146/annurev-pharmtox-010919-023429
111. Dhar R, Murphy-Human T. A bolus of conivaptan lowers intracranial pressure in a patient with hyponatremia after traumatic brain injury. Neurocrit Care. Feb 2011;14(1):97-102. doi:10.1007/s12028-010-9366-x
112. Fu Y, Hao J, Zhang N, et al. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol. Sep 2014;71(9):1092-101. doi:10.1001/jamaneurol.2014.1065
113. Li YJ, Chang GQ, Liu Y, et al. Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage. Neurosci Bull. Dec 2015;31(6):755-62. doi:10.1007/s12264-015-1532-2
114. Lee SH, Park HK, Ryu WS, et al. Effects of celecoxib on hematoma and edema volumes in primary intracerebral hemorrhage: a multicenter randomized controlled trial. Eur J Neurol. Aug 2013;20(8):1161-9. doi:10.1111/ene.12140
115. Kimberly WT, Bevers MB, von Kummer R, et al. Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial. Neurology. Dec 4 2018;91(23):e2163-e2169. doi:10.1212/WNL.0000000000006618
116. Sheth KN, Elm JJ, Molyneaux BJ, et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. Oct 2016;15(11):1160-9. doi:10.1016/S1474-4422(16)30196-X
117. Sheth KN, Petersen NH, Cheung K, et al. Long-Term Outcomes in Patients Aged 118. Jha RM, Bell J, Citerio G, et al. Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence. Int J Mol Sci. Jan 9 2020;21(2)
doi: 10.3390/ijms21020409