The Anaesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury

Summary

Cortical spreading depolarisations are pathological depolarisation waves that occur frequently after severe acute brain injury and has been associated with poor outcome. S-ketamine has been shown to inhibit cortical spreading depolarisations. The aim of the present study is to examine the efficacy and safety of using S-ketamine for treatment of patients with severe acute brain injury, as well as the feasibility of the trial design.

Timeline

Start

2023-09-15

Primary completion

2028-09-15

Completion

2028-09-15

Publications

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• Background Zhou YT, Tong DM, Wang SD, Ye S, Xu BW, Yang CX. Acute spontaneous intracerebral hemorrhage and traumatic brain injury are the most common causes of critical illness in the ICU and have high early mortality. BMC Neurol. 2018 Aug 27;18(1):127. doi: 10.1186/s12883-018-1127-z.
• Background Gross BA, Jankowitz BT, Friedlander RM. Cerebral Intraparenchymal Hemorrhage: A Review. JAMA. 2019 Apr 2;321(13):1295-1303. doi: 10.1001/jama.2019.2413.
• Background Gruenbaum SE, Zlotnik A, Gruenbaum BF, Hersey D, Bilotta F. Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury: A Systematic Review of the Clinical Literature. CNS Drugs. 2016 Sep;30(9):791-806. doi: 10.1007/s40263-016-0355-2.
• Background Gruenbaum SE, Bilotta F. Postoperative ICU management of patients after subarachnoid hemorrhage. Curr Opin Anaesthesiol. 2014 Oct;27(5):489-93. doi: 10.1097/ACO.0000000000000111.
• Background Seder DB, Mayer SA. Critical care management of subarachnoid hemorrhage and ischemic stroke. Clin Chest Med. 2009 Mar;30(1):103-22, viii-ix. doi: 10.1016/j.ccm.2008.11.004.
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• Background Shah S, Kimberly WT. Today's Approach to Treating Brain Swelling in the Neuro Intensive Care Unit. Semin Neurol. 2016 Dec;36(6):502-507. doi: 10.1055/s-0036-1592109. Epub 2016 Dec 1.
• Background Gradisek P, Osredkar J, Korsic M, Kremzar B. Multiple indicators model of long-term mortality in traumatic brain injury. Brain Inj. 2012;26(12):1472-81. doi: 10.3109/02699052.2012.694567. Epub 2012 Jun 21.
• Background Olsen MH, Orre M, Leisner ACW, Rasmussen R, Bache S, Welling KL, Eskesen V, Moller K. Delayed cerebral ischaemia in patients with aneurysmal subarachnoid haemorrhage: Functional outcome and long-term mortality. Acta Anaesthesiol Scand. 2019 Oct;63(9):1191-1199. doi: 10.1111/aas.13412. Epub 2019 Jun 7.
• Background Cordonnier C, Demchuk A, Ziai W, Anderson CS. Intracerebral haemorrhage: current approaches to acute management. Lancet. 2018 Oct 6;392(10154):1257-1268. doi: 10.1016/S0140-6736(18)31878-6.
• Background Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, Menon DK, Pickard JD, Kirkpatrick PJ. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014 Dec;85(12):1343-53. doi: 10.1136/jnnp-2014-307711. Epub 2014 May 20.
• Background Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011 Jan;31(1):17-35. doi: 10.1038/jcbfm.2010.191. Epub 2010 Nov 3.
• Background Hartings JA, Andaluz N, Bullock MR, Hinzman JM, Mathern B, Pahl C, Puccio A, Shutter LA, Strong AJ, Vagal A, Wilson JA, Dreier JP, Ngwenya LB, Foreman B, Pahren L, Lingsma H, Okonkwo DO. Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury. JAMA Neurol. 2020 Apr 1;77(4):489-499. doi: 10.1001/jamaneurol.2019.4476.
• Background Helbok R, Schiefecker AJ, Friberg C, Beer R, Kofler M, Rhomberg P, Unterberger I, Gizewski E, Hauerberg J, Moller K, Lackner P, Broessner G, Pfausler B, Ortler M, Thome C, Schmutzhard E, Fabricius M. Spreading depolarizations in patients with spontaneous intracerebral hemorrhage: Association with perihematomal edema progression. J Cereb Blood Flow Metab. 2017 May;37(5):1871-1882. doi: 10.1177/0271678X16651269. Epub 2016 Jan 1.
• Background Dreier JP, Woitzik J, Fabricius M, Bhatia R, Major S, Drenckhahn C, Lehmann TN, Sarrafzadeh A, Willumsen L, Hartings JA, Sakowitz OW, Seemann JH, Thieme A, Lauritzen M, Strong AJ. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain. 2006 Dec;129(Pt 12):3224-37. doi: 10.1093/brain/awl297. Epub 2006 Oct 25.
• Background Ayata C, Lauritzen M. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev. 2015 Jul;95(3):953-93. doi: 10.1152/physrev.00027.2014.
• Background Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, Jane JA, Marmarou A, Foulkes MA. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993 Feb;34(2):216-22. doi: 10.1097/00005373-199302000-00006.
• Background Welling L, Welling MS, Teixeira MJ, Figueiredo EG. Cortical spread depolarization and ketamine: a revival of an old drug or a new era of neuroprotective drugs? World Neurosurg. 2015 Apr;83(4):396-7. doi: 10.1016/j.wneu.2015.01.006. Epub 2015 Jan 31. No abstract available.
• Background Reinhart KM, Shuttleworth CW. Ketamine reduces deleterious consequences of spreading depolarizations. Exp Neurol. 2018 Jul;305:121-128. doi: 10.1016/j.expneurol.2018.04.007. Epub 2018 Apr 10.
• Background Sakowitz OW, Kiening KL, Krajewski KL, Sarrafzadeh AS, Fabricius M, Strong AJ, Unterberg AW, Dreier JP. Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury. Stroke. 2009 Aug;40(8):e519-22. doi: 10.1161/STROKEAHA.109.549303. Epub 2009 Jun 11.
• Background Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, Shutter LA, Vidgeon S, Strong AJ, Kowoll C, Dohmen C, Diedler J, Veltkamp R, Bruckner T, Unterberg AW, Sakowitz OW; Cooperative Study of Brain Injury Depolarizations (COSBID). Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain. 2012 Aug;135(Pt 8):2390-8. doi: 10.1093/brain/aws152. Epub 2012 Jun 19.
• Background Schiefecker AJ, Beer R, Pfausler B, Lackner P, Broessner G, Unterberger I, Sohm F, Mulino M, Thome C, Humpel C, Schmutzhard E, Helbok R. Clusters of cortical spreading depolarizations in a patient with intracerebral hemorrhage: a multimodal neuromonitoring study. Neurocrit Care. 2015 Apr;22(2):293-8. doi: 10.1007/s12028-014-0050-4.
• Background Hertle DN, Heer M, Santos E, Scholl M, Kowoll CM, Dohmen C, Diedler J, Veltkamp R, Graf R, Unterberg AW, Sakowitz OW. Changes in electrocorticographic beta frequency components precede spreading depolarization in patients with acute brain injury. Clin Neurophysiol. 2016 Jul;127(7):2661-7. doi: 10.1016/j.clinph.2016.04.026. Epub 2016 May 4.
• Background Carlson AP, Abbas M, Alunday RL, Qeadan F, Shuttleworth CW. Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial. J Neurosurg. 2018 May 25;130(5):1513-1519. doi: 10.3171/2017.12.JNS171665. Print 2019 May 1.
• Andreasen TH, Olsen MH, Gluud C, Lindschou J, Fabricius M, Hauerberg J, Moller K. S-ketamine versus placebo for cortical spreading depolarisation in severe acute brain injury (KETA-BID): protocol for a pilot, randomised, blinded clinical trial. BMJ Open. 2025 Jul 28;15(7):e101426. doi: 10.1136/bmjopen-2025-101426.

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