Consciousness, Unconsciousness
Conditions
Keywords
Sedation, Propofol, Dexmedetomidine, Ketamine, Sevoflurane, Electroencephalogram
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.
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.
Sponsors
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occipital Delta Power Spectral Density by Conscious State and Study Group. | Intraoperative (During sedation-- up to 8 hours) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World). | Intraoperative (During sedation-- up to 8 hours) | 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. |
| Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Intraoperative (During sedation-- up to 8 hours) | 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. |
| Effect of Study Drug on Ability to Correctly Identify Images | Intraoperative (During sedation-- up to 8 hours) | The ability to match sounds and images measured by the predictive coding task. Will be reported by a proportion correct as a decimal. |
| Effect of Study Drug on Ability to Form Implicit Memory | 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 average number of correct responses out of sixteen. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
Participants were assigned to a drug if they were both eligible and reconsented the morning of the visit. Drug visits occurred in a sequence: Dexmedetomidine, Ketamine, Propofol, and then Midazolam. The same participant could participate in all drug visits if they were eligible, and a minimum of 28 days had past since their previous drug visit. All participants interested in a drug visit were asked to also complete a sleep visit which occurred before the first drug visit if possible.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants completed sedation visits in the order of dexmedetomidine, ketamine, propofol, and midazolam. There was a washout period of at least 28 days between sedation visits. Subjects were also asked to complete a separate overnight sleep visit with an EEG. Participants reconsented at each sleep and sedation visit. If a patient was inappropriate for one sedative, due to a specific contraindication to that drug (and not the study in general) but were eligible for another drug, then they progressed through the order of sedatives while skipping that inappropriate drug.
At each drug visit, participants were fitted with a saline gel EEG cap and a pre-sedation recording was collected. Participants' brain waves were recorded during rest, while responding to a standardized wake report form, and while performing a predictive coding cognitive task on a computer. Once the pre-sedation recording was collected, the faculty anesthesiologist began administering the study drug. A new EEG recording was started to monitor brain waves while all of the pre-sedation activities were repeated after the administration of the study drug. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous Dexmedetomidine | 22.95 years STANDARD_DEVIATION 3.75 |
| Age, Continuous Ketamine | 21.47 years STANDARD_DEVIATION 3.14 |
| Age, Continuous Propofol | 22.83 years STANDARD_DEVIATION 4.17 |
| Age, Continuous Sleep | 25.13 years STANDARD_DEVIATION 5.33 |
| Age, Continuous Total | 23.44 years STANDARD_DEVIATION 4.6 |
| Ethnicity (NIH/OMB) Dexmedetomidine Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Dexmedetomidine Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Dexmedetomidine Unknown or Not Reported | 8 Participants |
| Ethnicity (NIH/OMB) Ketamine Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Ketamine Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Ketamine Unknown or Not Reported | 7 Participants |
| Ethnicity (NIH/OMB) Propofol Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Propofol Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Propofol Unknown or Not Reported | 4 Participants |
| Ethnicity (NIH/OMB) Sleep Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Sleep Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Sleep Unknown or Not Reported | 8 Participants |
| Ethnicity (NIH/OMB) Total Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Total Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Total Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) Dexmedetomidine American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Dexmedetomidine Asian | 1 Participants |
| Race (NIH/OMB) Dexmedetomidine Black or African American | 1 Participants |
| Race (NIH/OMB) Dexmedetomidine More than one race | 0 Participants |
| Race (NIH/OMB) Dexmedetomidine Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Dexmedetomidine Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) Dexmedetomidine White | 10 Participants |
| Race (NIH/OMB) Ketamine American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Ketamine Asian | 0 Participants |
| Race (NIH/OMB) Ketamine Black or African American | 0 Participants |
| Race (NIH/OMB) Ketamine More than one race | 0 Participants |
| Race (NIH/OMB) Ketamine Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Ketamine Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) Ketamine White | 8 Participants |
| Race (NIH/OMB) Propofol American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Propofol Asian | 0 Participants |
| Race (NIH/OMB) Propofol Black or African American | 0 Participants |
| Race (NIH/OMB) Propofol More than one race | 0 Participants |
| Race (NIH/OMB) Propofol Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Propofol Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) Propofol White | 2 Participants |
| Race (NIH/OMB) Sleep American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Sleep Asian | 1 Participants |
| Race (NIH/OMB) Sleep Black or African American | 1 Participants |
| Race (NIH/OMB) Sleep More than one race | 0 Participants |
| Race (NIH/OMB) Sleep Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Sleep Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) Sleep White | 4 Participants |
| Race (NIH/OMB) Total American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Total Asian | 1 Participants |
| Race (NIH/OMB) Total Black or African American | 2 Participants |
| Race (NIH/OMB) Total More than one race | 0 Participants |
| Race (NIH/OMB) Total Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Total Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) Total White | 15 Participants |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Dexmedetomidine Female | 6 Participants |
| Sex: Female, Male Dexmedetomidine Male | 14 Participants |
| Sex: Female, Male Ketamine Female | 5 Participants |
| Sex: Female, Male Ketamine Male | 10 Participants |
| Sex: Female, Male Propofol Female | 2 Participants |
| Sex: Female, Male Propofol Male | 4 Participants |
| Sex: Female, Male Sleep Female | 4 Participants |
| Sex: Female, Male Sleep Male | 11 Participants |
| Sex: Female, Male Total Female | 7 Participants |
| Sex: Female, Male Total Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 15 | 0 / 6 | 0 / 0 | 0 / 15 |
| other Total, other adverse events | 5 / 20 | 6 / 15 | 1 / 6 | 0 / 0 | 0 / 15 |
| serious Total, serious adverse events | 0 / 20 | 0 / 15 | 0 / 6 | 0 / 0 | 0 / 15 |
Outcome results
Primary
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)
Population: No midazolam visit was ever conducted because no interested participants had reached that step of the drug sequence after it was added to the protocol in November of 2019.This was in large part due to the shutdown of in-person research activities in March of 2020 from the COVID-19 pandemic.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Dexmedetomidine | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Unconsciousness | 2.68 log10(μV^2) |
| Dexmedetomidine | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Connected Consciousness | 2.37 log10(μV^2) |
| Dexmedetomidine | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Disconnected Consciousness | 2.57 log10(μV^2) |
| Ketamine | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Connected Consciousness | 1.62 log10(μV^2) |
| Ketamine | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Unconsciousness | 1.46 log10(μV^2) |
| Ketamine | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Disconnected Consciousness | 1.7 log10(μV^2) |
| Propofol | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Unconsciousness | 2.51 log10(μV^2) |
| Propofol | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Connected Consciousness | 2.05 log10(μV^2) |
| Propofol | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Disconnected Consciousness | 2.34 log10(μV^2) |
| Sleep | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Unconsciousness | 2.63 log10(μV^2) |
| Sleep | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Disconnected Consciousness | 2.58 log10(μV^2) |
| Sleep | Occipital Delta Power Spectral Density by Conscious State and Study Group. | Connected Consciousness | 2.1 log10(μV^2) |
Comparison: Dexmedetomidine, Unconsciousness vs Disconnected Consciousnessp-value: 0.012Mixed Models Analysis
Comparison: Ketamine, Unconsciousness vs Disconnected Consciousnessp-value: 0.236Mixed Models Analysis
Comparison: Propofol, Unconsciousness vs Disconnected Consciousnessp-value: 0.174Mixed Models Analysis
Comparison: Sleep, Unconsciousness vs Disconnected Consciousnessp-value: 0.64Mixed Models Analysis
Secondary
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)
Population: No data was collected for this outcome measure for Midazolam or Sleep
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexmedetomidine | Effect of Study Drug on Ability to Correctly Identify Images | Baseline Predictive Coding Task Accuracy | 0.916 proportion correct | Standard Deviation 0.07 |
| Dexmedetomidine | Effect of Study Drug on Ability to Correctly Identify Images | Sedation Predictive Coding Task Accuracy | 0.793 proportion correct | Standard Deviation 0.09 |
| Ketamine | Effect of Study Drug on Ability to Correctly Identify Images | Baseline Predictive Coding Task Accuracy | 0.899 proportion correct | Standard Deviation 0.07 |
| Ketamine | Effect of Study Drug on Ability to Correctly Identify Images | Sedation Predictive Coding Task Accuracy | 0.763 proportion correct | Standard Deviation 0.1 |
| Propofol | Effect of Study Drug on Ability to Correctly Identify Images | Baseline Predictive Coding Task Accuracy | 0.91 proportion correct | Standard Deviation 0.09 |
| Propofol | Effect of Study Drug on Ability to Correctly Identify Images | Sedation Predictive Coding Task Accuracy | 0.734 proportion correct | Standard Deviation 0.15 |
Comparison: Predictive Coding Task Accuracyp-value: <0.001t-test, 2 sided
Comparison: Predictive Coding Task Accuracyp-value: <0.001t-test, 2 sided
Comparison: Predictive Coding Task Accuracyp-value: 0.067t-test, 2 sided
Secondary
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)
Population: No data was collected for this outcome measure for Midazolam or Sleep
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexmedetomidine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Baseline NIH Toolbox Card Sorting Score | 8.83 score on a scale | Standard Deviation 1.21 |
| Dexmedetomidine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Sedation NIH Toolbox Card Sorting Score | 7.85 score on a scale | Standard Deviation 1.49 |
| Dexmedetomidine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Baseline NIH Toolbox Flanker Score | 9.14 score on a scale | Standard Deviation 0.67 |
| Dexmedetomidine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Sedation NIH Toolbox Flanker Score | 6.62 score on a scale | Standard Deviation 0.88 |
| Ketamine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Sedation NIH Toolbox Flanker Score | 8.47 score on a scale | Standard Deviation 0.93 |
| Ketamine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Baseline NIH Toolbox Card Sorting Score | 9.29 score on a scale | Standard Deviation 0.59 |
| Ketamine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Baseline NIH Toolbox Flanker Score | 8.99 score on a scale | Standard Deviation 0.83 |
| Ketamine | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Sedation NIH Toolbox Card Sorting Score | 8.2 score on a scale | Standard Deviation 0.99 |
| Propofol | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Sedation NIH Toolbox Flanker Score | 8.36 score on a scale | Standard Deviation 0.96 |
| Propofol | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Sedation NIH Toolbox Card Sorting Score | 6.94 score on a scale | Standard Deviation 4.16 |
| Propofol | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Baseline NIH Toolbox Flanker Score | 9.48 score on a scale | Standard Deviation 0.12 |
| Propofol | Effect of Study Drug on Ability to Correctly Identify Shapes/Images | Baseline NIH Toolbox Card Sorting Score | 9.45 score on a scale | Standard Deviation 0.95 |
Comparison: NIH Toolbox Card Sorting Scorep-value: 0.134t-test, 2 sided
Comparison: NIH Toolbox Card Sorting Scorep-value: 0.012t-test, 2 sided
Comparison: NIH Toolbox Card Sorting Scorep-value: 0.487t-test, 2 sided
Comparison: NIH Toolbox Flanker Scorep-value: 0.046t-test, 2 sided
Comparison: NIH Toolbox Flanker Scorep-value: 0.01t-test, 2 sided
Comparison: NIH Toolbox Flanker Scorep-value: 0.356t-test, 2 sided
Secondary
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)
Population: There was no data collected for this outcome measure for Midazolam or Sleep.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexmedetomidine | Effect of Study Drug on Ability to Form Implicit Memory | 8 correct responses | Standard Deviation 2.47 |
| Ketamine | Effect of Study Drug on Ability to Form Implicit Memory | 8.17 correct responses | Standard Deviation 1.7 |
| Propofol | Effect of Study Drug on Ability to Form Implicit Memory | 9 correct responses | Standard Deviation 1.58 |
Comparison: Null hypothesis is a 50% recall rate.p-value: 0.5t-test, 2 sided
Comparison: Null hypothesis is a 50% recall rate.p-value: 0.37t-test, 2 sided
Comparison: Null hypothesis is a 50% recall rate.p-value: 0.12t-test, 2 sided
Secondary
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)
Population: There was no data collected for Midazolam or Sleep for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dexmedetomidine | Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World). | Instances of Connected Consciousness | 70 number of instances |
| Dexmedetomidine | Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World). | Instances of Disconnected Consciousness | 226 number of instances |
| Ketamine | Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World). | Instances of Connected Consciousness | 180 number of instances |
| Ketamine | Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World). | Instances of Disconnected Consciousness | 30 number of instances |
| Propofol | Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World). | Instances of Connected Consciousness | 56 number of instances |
| Propofol | Number of Instances of Disconnected Conscious Experience (Dreaming) vs Connected Conscious Experience (Awareness of External World). | Instances of Disconnected Consciousness | 22 number of instances |