Spreading Depolarization and Ketamine Suppression

NCT02501941 | Completed Phase 1

• 1 other identifier: 15-056
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Cortical Spreading Depolarization; Cortical Spreading Depression; Subarachoid Hemorrhage; Traumatic Brain Injury

Keywords

Ketamine; Cortical Spreading Depolarization; Cortical Spreading Depression

Outcome Measures

Primary Outcomes (1)

• Change in frequency of Cortical Spreading depression with use of ketamine

  Frequency of events as defined by propagating slow potential change in adjacent leads with associated suppression of high frequency signal. Assessed by 2 experienced reviewers blinded to sedation arm.

  approximately 7 days

Secondary Outcomes (7)

• Change in frequency of Cortical Spreading depolarization with stimulation to patient

  approximately 7 days

• Change in frequency of Cortical Spreading depolarization with varying doses of ketamine

  approximately 7 days

• Presence of Scalp EEG tracings correlates to cortical spreading depolarization

  approximately 7 days

• Correlation between pre-operative neurologic exam (GCS) and amount and frequency of cortical spreading depolarizations

  approximately 7 days

• Correlation between post-operative neurologic exam (GCS) and amount and frequency of cortical spreading depolarizations

  approximately 7 days

Study Arms (2)

Ketamine first

EXPERIMENTAL

Randomization to receive ketamine as first post-operative sedative in the Neuroscience Intensive Care unit. This group will cross-over to "other sedation" after 6 hours, then alternate every 6 hours between these groups during the entirety of invasive neuromonitoring.

Drug: ketamine

Other sedation (typically propofol) first

EXPERIMENTAL

Randomization to receive sedative other than ketamine as first post-operative sedative in the Neuroscience Intensive Care unit. This group will cross-over to ketamine after 6 hours, then alternate every 6 hours between these groups during the entirety of invasive neuromonitoring.

Drug: ketamine

Interventions

ketamine DRUG

Ketamine will be used as a sedative alternative to other more conventional sedatives (such as propofol, versed, or dexmedetomidine) in 6 hour blocks of time. Ketamine will be titrated at the bedside based on clinically desired Riker Sedation-Agitation Scale target. Both groups will receive the drug in this multiple crossover design. The only difference between groups is which sedation regimen is started first to minimize any bias related to differences in physiology in the early post-operative phase.

Ketamine first; Other sedation (typically propofol) first

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• GCS \<8
• SAH or severe traumatic brain injury requiring craniotomy
• Consent obtainable (via legal representative)
• Ictus (bleed or injury) within 48 hours of enrollment
• Clinically appropriate for multimodality monitoring

You may not qualify if:

• Anticipated survival \<48 hours
• No craniotomy
• Infratentorial craniotomy only•Unable to obtain consent
• Absence of clinically used multimodality monitoring
• Prisoners
• Pregnant

Sponsors & Collaborators

• University of New Mexico: lead

Study Sites (1)

University of New Mexico

Albuquerque, New Mexico, 87131, United States

Location

Related Publications (25)

• 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.

  PMID: 22829393 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.

  PMID: 12468763 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.

  PMID: 16364954 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.

  PMID: 18496842 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.

  PMID: 24343564 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.

  PMID: 22366798 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.

  PMID: 25154587 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.

  PMID: 20504874 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.

  PMID: 19420089 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.

  PMID: 25154387 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.

  PMID: 20437558 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.

  PMID: 20145653 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.

  PMID: 17067993 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.

  PMID: 19508156 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.

  PMID: 22056157 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.

  PMID: 17327732 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.

  PMID: 24796257 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.

  PMID: 19520992 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.

  PMID: 22719001 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.

  PMID: 10446827 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.

  PMID: 14633551 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.

  PMID: 15367304 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.

  PMID: 15621365 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.

  PMID: 23982301 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.

  PMID: 29799344 RESULT

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Ketamine

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Andrew P Carlson, MD

  University of New Mexico

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: July 14, 2015
• First Posted: July 17, 2015
• Study Start: July 1, 2015
• Primary Completion: January 1, 2017
• Study Completion: May 1, 2017
• Last Updated: January 11, 2024

Record last verified: 2024-01

Locations

US (1)