CClinicalTrials.gg
CompletedNCT03284307UN-CONSCIOUSUpdated Apr 13, 2023Results posted

UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness Study

A Phase 4 interventional study of Dexmedetomidine and Ketamine in Unconsciousness and Consciousness, sponsored by University of Wisconsin, Madison. Completed at 1 site in United States. Open to participants aged 18 Years to 40 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-04-13.

Sponsored by University of Wisconsin, Madison · Phase 4, Interventional, and Basic science

Phase
Phase 4
Study type
Interventional
Enrollment
35
Allocation
Not applicable
Ages
18 Years to 40 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Unconsciousness
  • Consciousness

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Keywords

  • Sedation
  • Propofol
  • Dexmedetomidine
  • Ketamine
  • Sevoflurane
  • Electroencephalogram
03

Who can participate

Ages eligible
18 Years to 40 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

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
04

Study design

Phase
Phase 4
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
35 participants (actual)

Study arms

  • Experimental
    Drug Administrated

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

    Drug: Dexmedetomidine · Drug: Ketamine · Drug: Propofol · Drug: Midazolam

Interventions

  • DrugDexmedetomidine

    20 participants will be administered Dexmedetomidine.

  • DrugKetamine

    20 participants will be administered Ketamine.

  • DrugPropofol

    20 participants will be administered Propofol.

  • DrugMidazolam

    20 participants will be administered Midazolam.

05

What researchers measure

Primary outcomes

  1. Occipital Delta Power Spectral Density by Conscious State and Study Group.

    The difference in spontaneous EEG slow wave activity over posterior cortex between states of consciousness measured with high-density EEG equipment and reported in spectral power in the delta band (1-4 Hz) at electrode Oz. Disconnected conscious experience (dreaming), connected conscious experience (awareness of the external world), and unconsciousness (no report) was assessed when participants were roused from sedation or sleep.

    Time frame: Intraoperative (During sedation-- up to 8 hours)

Secondary outcomes

  1. Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World).

    The number of instances 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.

    Time frame: Intraoperative (During sedation-- up to 8 hours)

  2. Effect of Study Drug on Ability to Correctly Identify Shapes/Images

    The ability to identify shapes/images in visual illusions measured by the NIH Toolbox. Will be reported by a computed score from NIH Toolbox for the Dimensional Change Card Sort Test (DCCS) and the Flanker Inhibitory Control \& Attention Test (Flanker). Both Flanker and DCCS use a 2-vector scoring method that takes accuracy and reaction time (if accuracy \>=80%) into account, resulting in a computed score that can range in value from 0-10. A higher score indicates better performance on the test.

    Time frame: Intraoperative (During sedation-- up to 8 hours)

  3. Effect of Study Drug on Ability to Correctly Identify Images

    The ability to match sounds and images measured by the predictive coding task. Will be reported by a proportion correct as a decimal.

    Time frame: Intraoperative (During sedation-- up to 8 hours)

  4. Effect of Study Drug on Ability to Form Implicit Memory

    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 average number of correct responses out of sixteen.

    Time frame: Intraoperative (During sedation-- up to 8 hours)

06

Results

Posted Apr 10, 2023
Limitations and caveats
The fourth study drug was changed from sevoflurane to midazolam in November of 2019 due to concerns about conducting experiments in patients inhaling a volatile anesthetic through a face mask and the difficulty we would have with communicating with patients. The cessation of human subjects research due to the COVID-19 pandemic and amended institutional guidelines for conducting in-person research caused far fewer participants to be recruited than was planned.

Participant flow

Participants were recruited via an email that was sent to UW-Madison students and staff from August 2017 through March 2020. Interested participants would discuss study commitment and preliminary screening criteria with the study team over the phone. Eligible participants would meet with a faculty anesthesiologist at a screening visit to complete informed consent and for a history and physical examination and basic neuropsychological assessment to determine subsequent study visit eligibility.

Participant flow — Overall Study
MilestoneAll Study Participants
Started35
Completed sedation and/or sleep visit27
Completed sedation visit21
Sleep15
Dexmedetomidine20
Ketamine15
Propofol6
Midazolam0
Completed27
Not completed8

Outcome measures

PrimaryOccipital Delta Power Spectral Density by Conscious State and Study Group.

The difference in spontaneous EEG slow wave activity over posterior cortex between states of consciousness measured with high-density EEG equipment and reported in spectral power in the delta band (1-4 Hz) at electrode Oz. Disconnected conscious experience (dreaming), connected conscious experience (awareness of the external world), and unconsciousness (no report) was assessed when participants were roused from sedation or sleep.

Time frame:
Intraoperative (During sedation-- up to 8 hours)
Reported as:
Least squares mean · log10(μV^2)
Occipital Delta Power Spectral Density by Conscious State and Study Group.
log10(μV^2)DexmedetomidineKetaminePropofolMidazolamSleep
Connected Consciousness2.37 (2.31 to 2.46)1.62 (1.57 to 1.68)2.05 (1.94 to 2.15)—2.1 (2.03 to 2.18)
Disconnected Consciousness2.57 (2.53 to 2.61)1.7 (1.57 to 1.84)2.34 (2.22 to 2.5)—2.58 (2.52 to 2.65)
Unconsciousness2.68 (2.61 to 2.75)1.46 (1.16 to 1.83)2.51 (2.31 to 2.68)—2.63 (2.47 to 2.83)
Statistical analysis
  • Dexmedetomidine · Mixed Models Analysis · p = 0.012 (Statistical significance defined by p \< 0.05.) · Slope: 0.110Estimate is a slope from a linear mixed effects model representing the difference in occipital delta power between unconsciousness and disconnected consciousness after adjusting for within-subject effects.
  • Ketamine · Mixed Models Analysis · p = 0.236 (Statistical significance defined by p \< 0.05.) · Slope: -0.238Estimate is a slope from a linear mixed effects model representing the difference in occipital delta power between unconsciousness and disconnected consciousness after adjusting for within-subject effects.
  • Propofol · Mixed Models Analysis · p = 0.174 (Statistical significance defined by p \< 0.05.) · Slope: 0.166Estimate is a slope from a linear mixed effects model representing the difference in occipital delta power between unconsciousness and disconnected consciousness after adjusting for within-subject effects.
  • Sleep · Mixed Models Analysis · p = 0.640 (Statistical significance defined by p \< 0.05.) · Slope: 0.052Estimate is a slope from a linear mixed effects model representing the difference in occipital delta power between unconsciousness and disconnected consciousness after adjusting for within-subject effects.
SecondaryNumber of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World).

The number of instances 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.

Time frame:
Intraoperative (During sedation-- up to 8 hours)
Reported as:
Number · number of instances
Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World).
number of instancesDexmedetomidineKetaminePropofolMidazolamSleep
Instances of Connected Consciousness7018056——
Instances of Disconnected Consciousness2263022——
SecondaryEffect of Study Drug on Ability to Correctly Identify Shapes/Images

The ability to identify shapes/images in visual illusions measured by the NIH Toolbox. Will be reported by a computed score from NIH Toolbox for the Dimensional Change Card Sort Test (DCCS) and the Flanker Inhibitory Control \& Attention Test (Flanker). Both Flanker and DCCS use a 2-vector scoring method that takes accuracy and reaction time (if accuracy \>=80%) into account, resulting in a computed score that can range in value from 0-10. A higher score indicates better performance on the test.

Time frame:
Intraoperative (During sedation-- up to 8 hours)
Reported as:
Mean · score on a scale
Effect of Study Drug on Ability to Correctly Identify Shapes/Images
score on a scaleDexmedetomidineKetaminePropofolMidazolamSleep
Baseline NIH Toolbox Card Sorting Score8.83 ± 1.219.29 ± 0.599.45 ± 0.95——
Sedation NIH Toolbox Card Sorting Score7.85 ± 1.498.2 ± 0.996.94 ± 4.16——
Baseline NIH Toolbox Flanker Score9.14 ± 0.678.99 ± 0.839.48 ± 0.12——
Sedation NIH Toolbox Flanker Score6.62 ± 0.888.47 ± 0.938.36 ± 0.96——
Statistical analysis
  • Dexmedetomidine · t-test, 2 sided · p = 0.134 (Statistical significance defined by p \< 0.05.)3 degrees of freedom
  • Ketamine · t-test, 2 sided · p = 0.012 (Statistical significance defined by p \< 0.05.)6 degrees of freedom
  • Propofol · t-test, 2 sided · p = 0.487 (Statistical significance defined by p \< 0.05.)1 degree of freedom
  • Dexmedetomidine · t-test, 2 sided · p = 0.046 (Statistical significance defined by p \< 0.05.)3 degrees of freedom
  • Ketamine · t-test, 2 sided · p = 0.010 (Statistical significance defined by p \< 0.05.)6 degrees of freedom
  • Propofol · t-test, 2 sided · p = 0.356 (Statistical significance defined by p \< 0.05.)
SecondaryEffect of Study Drug on Ability to Correctly Identify Images

The ability to match sounds and images measured by the predictive coding task. Will be reported by a proportion correct as a decimal.

Time frame:
Intraoperative (During sedation-- up to 8 hours)
Reported as:
Mean · proportion correct
Effect of Study Drug on Ability to Correctly Identify Images
proportion correctDexmedetomidineKetaminePropofolMidazolamSleep
Baseline Predictive Coding Task Accuracy0.916 ± 0.070.899 ± 0.070.91 ± 0.09——
Sedation Predictive Coding Task Accuracy0.793 ± 0.090.763 ± 0.10.734 ± 0.15——
Statistical analysis
  • Dexmedetomidine · t-test, 2 sided · p = <0.001 (Statistical significance defined by p \< 0.05.)17 degrees of freedom
  • Ketamine · t-test, 2 sided · p = <0.001 (Statistical significance defined by p \< 0.05.)14 degrees of freedom
  • Propofol · t-test, 2 sided · p = 0.067 (Statistical significance defined by p \< 0.05.)4 degrees of freedom
SecondaryEffect of Study Drug on Ability to Form Implicit Memory

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 average number of correct responses out of sixteen.

Time frame:
Intraoperative (During sedation-- up to 8 hours)
Reported as:
Mean · correct responses
Effect of Study Drug on Ability to Form Implicit Memory
correct responsesDexmedetomidineKetaminePropofolMidazolamSleep
Effect of Study Drug on Ability to Form Implicit Memory8 ± 2.478.17 ± 1.709 ± 1.58——
Statistical analysis
  • Dexmedetomidine · t-test, 2 sided · p = 0.5 (Statistical significance defined by p \< 0.05.)17 degrees of freedom
  • Ketamine · t-test, 2 sided · p = 0.37 (Statistical significance defined by p \< 0.05.)11 degrees of freedom
  • Propofol · t-test, 2 sided · p = 0.12 (Statistical significance defined by p \< 0.05.)4 degrees of freedom

Adverse events

Collected over 24 hours after drug or sleep visit.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Dexmedetomidine0/20 (0%)0/20 (0%)5/20 (25%)
Ketamine0/15 (0%)0/15 (0%)6/15 (40%)
Propofol0/6 (0%)0/6 (0%)1/6 (16.7%)
Midazolam———
Sleep0/15 (0%)0/15 (0%)0/15 (0%)
Most frequent other events
Most frequent other events
EventDexmedetomidineKetaminePropofolMidazolamSleep
VomitingGastrointestinal disorders1/204/150/6—0/15
BruisingInjury, poisoning and procedural complications0/201/151/6—0/15
NauseaGastrointestinal disorders1/202/150/6—0/15
HypotensionCardiac disorders1/200/150/6—0/15
BradycardiaCardiac disorders1/200/150/6—0/15
Mild Chest PainCardiac disorders1/200/150/6—0/15
Pain at injection siteInjury, poisoning and procedural complications1/200/150/6—0/15
HeadacheNervous system disorders1/200/150/6—0/15

Baseline characteristics

All participants who completed a sleep and/or sedation visit.

Age, Continuous
Age, Continuous(years)All Study Participants
Total23.44 ± 4.60
Sleep25.13 ± 5.33
Dexmedetomidine22.95 ± 3.75
Ketamine21.47 ± 3.14
Propofol22.83 ± 4.17
Sex: Female, Male
Sex: Female, Male(Participants)All Study Participants
Total — Female7
Total — Male20
Sleep — Female4
Sleep — Male11
Dexmedetomidine — Female6
Dexmedetomidine — Male14
Ketamine — Female5
Ketamine — Male10
Propofol — Female2
Propofol — Male4
Midazolam — Female—
Midazolam — Male—
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)All Study Participants
Total — Hispanic or Latino2
Total — Not Hispanic or Latino17
Total — Unknown or Not Reported8
Sleep — Hispanic or Latino1
Sleep — Not Hispanic or Latino6
Sleep — Unknown or Not Reported8
Dexmedetomidine — Hispanic or Latino1
Dexmedetomidine — Not Hispanic or Latino11
Dexmedetomidine — Unknown or Not Reported8
Ketamine — Hispanic or Latino1
Ketamine — Not Hispanic or Latino7
Ketamine — Unknown or Not Reported7
Propofol — Hispanic or Latino0
Propofol — Not Hispanic or Latino2
Propofol — Unknown or Not Reported4
Midazolam — Hispanic or Latino—
Midazolam — Not Hispanic or Latino—
Midazolam — Unknown or Not Reported—
Race (NIH/OMB)
Race (NIH/OMB)(Participants)All Study Participants
Total — American Indian or Alaska Native0
Total — Asian1
Total — Native Hawaiian or Other Pacific Islander1
Total — Black or African American2
Total — White15
Total — More than one race0
Total — Unknown or Not Reported8
Sleep — American Indian or Alaska Native0
Sleep — Asian1
Sleep — Native Hawaiian or Other Pacific Islander1
Sleep — Black or African American1
Sleep — White4
Sleep — More than one race0
Sleep — Unknown or Not Reported8
Dexmedetomidine — American Indian or Alaska Native0
Dexmedetomidine — Asian1
Dexmedetomidine — Native Hawaiian or Other Pacific Islander0
Dexmedetomidine — Black or African American1
Dexmedetomidine — White10
Dexmedetomidine — More than one race0
Dexmedetomidine — Unknown or Not Reported8
Ketamine — American Indian or Alaska Native0
Ketamine — Asian0
Ketamine — Native Hawaiian or Other Pacific Islander0
Ketamine — Black or African American0
Ketamine — White8
Ketamine — More than one race0
Ketamine — Unknown or Not Reported7
Propofol — American Indian or Alaska Native0
Propofol — Asian0
Propofol — Native Hawaiian or Other Pacific Islander0
Propofol — Black or African American0
Propofol — White2
Propofol — More than one race0
Propofol — Unknown or Not Reported4
Midazolam — American Indian or Alaska Native—
Midazolam — Asian—
Midazolam — Native Hawaiian or Other Pacific Islander—
Midazolam — Black or African American—
Midazolam — White—
Midazolam — More than one race—
Midazolam — Unknown or Not Reported—
Region of Enrollment
Region of Enrollment(participants)All Study Participants
United States27
07

Study locations

1 site
  • UW Hospital and Clinics
    Madison, Wisconsin 53792, United States
08

References and documents

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. PubMed 35148892 ↗

Study documents

  • Protocol and statistical analysis plan · Jan 11, 2023
  • Informed consent form · May 15, 2020

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03284307
Lead sponsor
University of Wisconsin, Madison
Responsible party
Sponsor
First posted
Sep 15, 2017
Start date
Aug 10, 2017
Primary completion
Mar 12, 2020
Completion
Mar 12, 2020
Results posted
Apr 10, 2023
Last update
Apr 13, 2023

Study contacts

Robert A Pearce, MD, PhD
principal investigator · Professor and chair of Anesthesiology at UW- Madison

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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