UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness Study (UN-CONSCIOUS)

• ClinicalTrials.gov Identifier: NCT03284307
• Recruitment Status: Active, not recruiting
• First Posted: September 15, 2017
• Last Update Posted: October 8, 2021
• Sponsor: University of Wisconsin, Madison
• Information provided by (Responsible Party): University of Wisconsin, Madison

Tracking Information

• First Submitted Date: August 22, 2017
• First Posted Date: September 15, 2017
• Last Update Posted Date: October 8, 2021
• Actual Study Start Date: August 10, 2017
• Estimated Primary Completion Date: August 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 17, 2020)

Spontaneous EEG slow wave activity [ Time Frame: Intraoperative (During sedation-- up to 8 hours) ]

The difference in spontaneous EEG slow wave activity over posterior cortex between consciousness and unconsciousness is measured with high-density EEG equipment and reported in spectral power in the delta band at electrode Oz.

Original Primary Outcome Measures (submitted: September 14, 2017)

Spontaneous EEG slow wave activity [ Time Frame: Intraoperative (During sedation) ]

Investigate the difference in spontaneous EEG slow wave activity over posterior cortex between consciousness and unconsciousness.

Current Secondary Outcome Measures (submitted: June 17, 2020)

• Incidence of disconnected conscious experience (dreaming) vs connected conscious experience (awareness of external world). [ Time Frame: Intraoperative (During sedation-- up to 8 hours) ]
  The incidence of disconnected conscious experience (dreaming) versus connected conscious experience (awareness of the external world) during sedation is measured by subject self-report at the time of researcher initiated inquiry.
• Difference in high-density EEG responses assessed by calculation of the phase locking factor following auditory stimulation [ Time Frame: Intraoperative (During sedation-- up to 8 hours) ]
  Difference in high-density EEG responses assessed by calculation of the phase locking factor following auditory stimulation between conscious experience under sedation and lack of conscious experience. Phase locking factor is calculated by taking the Hilbert transform of the evoked response and quantifying the alignment of phases based on the imaginary component of the signal. Phase locking factor is quantified on a scale of 0 to 1, with 0 being no phase locking and 1 being maximal phase locking.
• Effect of study drug on percent difference in duration of phase locking factor [ Time Frame: Intraoperative (During sedation-- up to 8 hours) ]
  Phase locking factor will be calculated (as described previously) and compared between data collected at baseline and data collected after varying doses of drug have been administered. Effect size will be reported as a percentage of the reference group.
• Effect of consciousness on phase locking factor after auditory stimulation [ Time Frame: Intraoperative (During sedation-- up to 8 hours) ]
  Phase locking factor will be calculated (as described previously) and compared between data collected during different states of consciousness (as assessed by subject report). Effect size will be reported as a percentage of the reference group.
• Effect of study drug on ability to correctly identify shapes/images [ Time Frame: Intraoperative (During sedation-- up to 8 hours) ]
  The ability to identify shapes/images in visual illusions measured by the NIH Toolbox and match sounds and images measured by the predictive coding task. Will be reported by a percent correct from the predictive coding task and total score from NIH Toolbox.
• Effect of study drug on ability to form implicit memory [ Time Frame: Intraoperative (During sedation-- up to 8 hours) ]
  Subjects will have a list of words read to them while under sedation and their ability to hear these words and form implicit memories of them will be assessed using a two-alternative forced choice task. Results will be reported as the number correct responses out of sixteen.
• Incidence of EEG wave patterns during sedation vs natural sleep [ Time Frame: Intraoperative (During sedation and sleep visit-- up to 18 hours cumulative) ]
  Low frequency (<4 Hz) spectral power will be measured using high-density EEG acquired during natural sleep as well as during sedation. The magnitude of this spectral power will be compared across conditions and reported as a percentage relative to natural sleep.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness Study
• Official Title: UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness Study
• Brief Summary: This study will be a single-site, controlled, unblinded study at the University of Wisconsin to examine changes in the electroencephalogram during anesthesia and waking.

Detailed Description

* 20 subjects will be recruited per drug, and subjects can be recruited to undergo multiple sedation protocols.

Screening:

Subjects will respond to the volunteer posts for the study by calling into a study specific phone number. They will complete a phone screening to determine basic eligibility for the study. At the beginning of the sedation session, participants will affirm that in the interval since their baseline visit, they have not acquired any of the cited exclusion criteria that would preclude participation. A review of these exclusion criteria will be completed by the Anesthesiologist. A standard pre-anesthetic assessment will be performed, including confirmation of NPO status, and documented using the standard Department of Anesthesiology pre-operative evaluation form.

The first sedative will be dexmedetomidine followed by ketamine, propofol and then midazolam (dependent on the availability of the drugs). Total enrollment in the study will be up to 80 subjects. Each sedation experiment will occur on separate days at least 28 days apart, if the subject chooses to participate in more than one session.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science

Condition

• Unconsciousness
• Consciousness

Intervention

• Drug: Dexmedetomidine
  20 participants will be administered Dexmedetomidine.
• Drug: Ketamine
  20 participants will be administered Ketamine.
• Drug: Propofol
  20 participants will be administered Propofol.
• Drug: Midazolam
  20 participants will be administered Midazolam.

Study Arms

Experimental: Drug Administrated

Sedatives will be administered to participants while their brain activity is measured.

Interventions:

• Drug: Dexmedetomidine
• Drug: Ketamine
• Drug: Propofol
• Drug: Midazolam

• Publications *: Casey CP, Tanabe S, Farahbakhsh Z, Parker M, Bo A, White M, Ballweg T, Mcintosh A, Filbey W, Saalmann Y, Pearce RA, Sanders RD. Distinct EEG signatures differentiate unconsciousness and disconnection during anaesthesia and sleep. Br J Anaesth. 2022 Jun;128(6):1006-1018. doi: 10.1016/j.bja.2022.01.010. Epub 2022 Feb 9.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 2, 2021): 30
• Original Estimated Enrollment (submitted: September 14, 2017): 80
• Estimated Study Completion Date: August 2022
• Estimated Primary Completion Date: August 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age 18-40
• In good health, determined by the PI on the basis of medical history and a standard assessment for anesthesia to be documented as part of the study record
• Right handed, to standardize for asymmetry in brain functions

Exclusion Criteria:

• Adults <18 years old or >40 years old
• Pregnancy confirmed on pregnancy test on day of sedation
• Contraindication to anesthesia or allergy to study drug

• Difficult anesthesia: American Society of Anesthesiologists Physical Status greater than 1, per the discretion of the PI. Examples of ASA status include, but are not limited to:

  • Any systemic disease present, such as diabetes, cardiac, pulmonary, or other acute or chronic disorder, or history of smoking
  • Narrow angle glaucoma
  • Abnormal airway examination
  • Any abnormality on medical history and physical examination
  • Snoring or sleep disorders including apnea
  • Antecedent pulmonary aspiration risk (e.g., history GI reflux, heartburn, hiatal hernia)
  • Adverse reaction or allergy with anesthesia or other sedatives
  • Chronic medication use
  • History of difficult anesthesia, laryngoscopy or intubation
  • Family history of difficulty with anesthesia or sedation
  • History of vertigo, nausea or vomiting after anesthesia
• BMI > 35
• Contraindication to HD-EEG, TMS or MRI for relative parts of the procedures. MRI exclusion criteria: presence of metallic or electronic implants; history of claustrophobia. TMS exclusion criteria: Presence or history of medical conditions that could increase the chance of seizures (e.g. - stroke, aneurysm, brain surgery, structural brain lesion) cranial metal implants; structural brain lesion; devices that may be affected by TMS (pacemaker, medication pump, cochlear implant, implanted brain stimulator); history of head trauma with loss of consciousness for greater than 5 minutes; family history of seizures; history of antecedent mood disorder.

• Exclusion from Dexmedetomidine:

  o Resting heart Rate<60 bpm

• Exclusion from Propofol:

  o Reported egg allergy

• Exclusion from Ketamine:

  • History of post-operative nausea and vomiting
  • History of motion sickness

Additional exclusion criteria on the day of sedation:

• Anything to eat or drink for the preceding 8 hours
• Any use of over-the-counter or recreational drugs (including alcohol or tobacco) within the preceding 24 hours
• Any use of sedative or sleep agents within the preceding 24 hours
• Recent change in health, including cough, cold, or fever
• Exposure to anesthesia or sedation in the last 6 days

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 40 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03284307
• Other Study ID Numbers: 2015-1399; A530900 ( Other Identifier: UW Madison ); SMPH\ANESTHESIOLOGY\ANESTHESIO ( Other Identifier: UW Madison ); Protocol Version 10/18/2019 ( Other Identifier: UW Madison )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: University of Wisconsin, Madison
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Wisconsin, Madison
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Robert A Pearce, MD, PhD; Professor and chair of Anesthesiology at UW- Madison

• PRS Account: University of Wisconsin, Madison
• Verification Date: October 2021