Spreading Depolarization and Ketamine Suppression

Summary

Hypothesis: Cortical spreading depolarizations are inhibited by the NMDA receptor antagonist Ketamine Aim 1: To demonstrate, in a group of patients with acute severe brain injury requiring surgery including traumatic brain injury and aneurysmal subarachnoid hemorrhage, whether use of continuous infusion of ketamine decreases frequency of occurrence of cortical spreading depolarizations.

Timeline

Start

2015-07

Primary completion

2017-01-01

Completion

2017-05-01

Publications

• Background Dreier JP, Isele T, Reiffurth C, Offenhauser N, Kirov SA, Dahlem MA, Herreras O. Is spreading depolarization characterized by an abrupt, massive release of gibbs free energy from the human brain cortex? Neuroscientist. 2013 Feb;19(1):25-42. doi: 10.1177/1073858412453340. Epub 2012 Jul 24.
• Background Strong AJ, Fabricius M, Boutelle MG, Hibbins SJ, Hopwood SE, Jones R, Parkin MC, Lauritzen M. Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke. 2002 Dec;33(12):2738-43. doi: 10.1161/01.str.0000043073.69602.09.
• Background Fabricius M, Fuhr S, Bhatia R, Boutelle M, Hashemi P, Strong AJ, Lauritzen M. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain. 2006 Mar;129(Pt 3):778-90. doi: 10.1093/brain/awh716. Epub 2005 Dec 19.
• Background Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, Brinker G, Dreier JP, Woitzik J, Strong AJ, Graf R; Co-Operative Study of Brain Injury Depolarisations (COSBID). Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol. 2008 Jun;63(6):720-8. doi: 10.1002/ana.21390.
• Background Jeffcote T, Hinzman JM, Jewell SL, Learney RM, Pahl C, Tolias C, Walsh DC, Hocker S, Zakrzewska A, Fabricius ME, Strong AJ, Hartings JA, Boutelle MG. Detection of spreading depolarization with intraparenchymal electrodes in the injured human brain. Neurocrit Care. 2014 Feb;20(1):21-31. doi: 10.1007/s12028-013-9938-7.
• Background Drenckhahn C, Winkler MK, Major S, Scheel M, Kang EJ, Pinczolits A, Grozea C, Hartings JA, Woitzik J, Dreier JP; COSBID study group. Correlates of spreading depolarization in human scalp electroencephalography. Brain. 2012 Mar;135(Pt 3):853-68. doi: 10.1093/brain/aws010.
• Background Hartings JA, Wilson JA, Hinzman JM, Pollandt S, Dreier JP, DiNapoli V, Ficker DM, Shutter LA, Andaluz N. Spreading depression in continuous electroencephalography of brain trauma. Ann Neurol. 2014 Nov;76(5):681-94. doi: 10.1002/ana.24256. Epub 2014 Sep 17.
• Background Nakamura H, Strong AJ, Dohmen C, Sakowitz OW, Vollmar S, Sue M, Kracht L, Hashemi P, Bhatia R, Yoshimine T, Dreier JP, Dunn AK, Graf R. Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain. 2010 Jul;133(Pt 7):1994-2006. doi: 10.1093/brain/awq117. Epub 2010 May 26.
• Background Dreier JP, Major S, Manning A, Woitzik J, Drenckhahn C, Steinbrink J, Tolias C, Oliveira-Ferreira AI, Fabricius M, Hartings JA, Vajkoczy P, Lauritzen M, Dirnagl U, Bohner G, Strong AJ; COSBID study group. Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain. 2009 Jul;132(Pt 7):1866-81. doi: 10.1093/brain/awp102. Epub 2009 May 6.
• Background Hinzman JM, Andaluz N, Shutter LA, Okonkwo DO, Pahl C, Strong AJ, Dreier JP, Hartings JA. Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain. 2014 Nov;137(Pt 11):2960-72. doi: 10.1093/brain/awu241. Epub 2014 Aug 24.
• Background Bosche B, Graf R, Ernestus RI, Dohmen C, Reithmeier T, Brinker G, Strong AJ, Dreier JP, Woitzik J; Members of the Cooperative Study of Brain Injury Depolarizations (COSBID). Recurrent spreading depolarizations after subarachnoid hemorrhage decreases oxygen availability in human cerebral cortex. Ann Neurol. 2010 May;67(5):607-17. doi: 10.1002/ana.21943.
• Background Feuerstein D, Manning A, Hashemi P, Bhatia R, Fabricius M, Tolias C, Pahl C, Ervine M, Strong AJ, Boutelle MG. Dynamic metabolic response to multiple spreading depolarizations in patients with acute brain injury: an online microdialysis study. J Cereb Blood Flow Metab. 2010 Jul;30(7):1343-55. doi: 10.1038/jcbfm.2010.17. Epub 2010 Feb 10.
• 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 Hartings JA, Strong AJ, Fabricius M, Manning A, Bhatia R, Dreier JP, Mazzeo AT, Tortella FC, Bullock MR; Co-Operative Study of Brain Injury Depolarizations. Spreading depolarizations and late secondary insults after traumatic brain injury. J Neurotrauma. 2009 Nov;26(11):1857-66. doi: 10.1089/neu.2009.0961.
• Background Hartings JA, Bullock MR, Okonkwo DO, Murray LS, Murray GD, Fabricius M, Maas AI, Woitzik J, Sakowitz O, Mathern B, Roozenbeek B, Lingsma H, Dreier JP, Puccio AM, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarisations. Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study. Lancet Neurol. 2011 Dec;10(12):1058-64. doi: 10.1016/S1474-4422(11)70243-5. Epub 2011 Nov 3.
• Background Strong AJ, Hartings JA, Dreier JP. Cortical spreading depression: an adverse but treatable factor in intensive care? Curr Opin Crit Care. 2007 Apr;13(2):126-33. doi: 10.1097/MCC.0b013e32807faffb.
• Background Sanchez-Porras R, Santos E, Scholl M, Stock C, Zheng Z, Schiebel P, Orakcioglu B, Unterberg AW, Sakowitz OW. The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex. Neuropharmacology. 2014 Sep;84:52-61. doi: 10.1016/j.neuropharm.2014.04.018. Epub 2014 May 4.
• 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 Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999 Jul;27(7):1325-9. doi: 10.1097/00003246-199907000-00022.
• Background Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesth Analg. 2003 Dec;97(6):1730-1739. doi: 10.1213/01.ANE.0000086618.28845.9B.
• Background Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med. 2004 Sep;5(3):263-75. doi: 10.1111/j.1526-4637.2004.04043.x.
• Background Elia N, Tramer MR. Ketamine and postoperative pain--a quantitative systematic review of randomised trials. Pain. 2005 Jan;113(1-2):61-70. doi: 10.1016/j.pain.2004.09.036.
• Background Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42. doi: 10.1176/appi.ajp.2013.13030392.
• Results 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.

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Indications