Clinical trial NCT03553758
Conditions: Anesthesia
Sponsor: Massachusetts General Hospital
Start date: 2018-11-01; Completion date: 2019-08-01
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
We are doing this research study to find out how and where ketamine acts in the brain. Ketamine is an anesthetic (a drug or agent used to decrease or eliminate the feeling of pain by putting you in an unconscious state). We will look at the brain using a machine that records the brain's electrical activity, called an electroencephalogram (EEG). We will assess how it impacts patient's pain responses.

Detailed description:
In this trial, participants will be given ketamine at a high enough dosage to induce general anesthesia. EEG recording will be conducted during this time. Cognitive assessments and pain monitoring will be administered at various points before and after ketamine induction.

Arms: arm 1: 15 subjects undergoing ketamine general anesthesia.
Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: Subjects' brain waves will be monitored by EEG recording under ketamine general anesthesia over the course of approximately 60 minutes. Patients pain and dissociation will be assessed before the induction of ketamine and periodically after. Approximately 1 hour after ketamine induction, Midazolam will be administered to reduce patient dissociation.

Protocol documents:
Prot_SAP_001.pdf: 
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Electroencephalogram Studies of Induction and Recovery from Ketamine-Induced General Anesthesia  
 
NCT 03553758 
5/11/2018 


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Electroencephalogram Studies of Induction and Recovery from Ketamine-Induced General Anesthesia 
 
Principal Investigator: Oluwaseun Johnson-Akeju, M.D., M.M.Sc 
 
1. BACKGROUND AND SIGNIFICANCE 
General anesthesia is a man-made, neurophysiological phenomenon that has been developed 
empirically to enable the safe and humane performance of surgical and non-surgical procedures. The state 
consists of unconsciousness, amnesia, analgesia, and immobility along with maintenance of physiological 
stability.1 Although general anesthesia is a neurophysiological phenomenon, until recently, approaches to 
studying the mechanisms of anesthetic action have focused primarily on characterizing the actions of these 
agents at molecular targets in the brain and spinal cord.2-5 This important work has identified common 
molecular and pharmacological principles of anesthetics and has established that there are several rather than 
a single mechanism of anesthetic action.6,7 Characterization of pharmacokinetic and pharmacodynamic 
properties, another focus of anesthesia drug research, has provided the guidelines for anesthetic drug dosing.8 
A considerable gap lies between knowing the multiple targets to which anesthetics bind, their pharmacological 
properties, and stating how actions at these targets lead to any behavioral state of general anesthesia. This is 
a problem in systems neuroscience as it requires defining how the stimulus (the anesthetic) acts in specific 
neural circuits to produce one or more behavioral states (unconsciousness, amnesia, analgesia, immobility).9 
 
Human Studies of Anesthesia 
In recent years, aided largely by non-invasive imaging methods, significant progress has been made in 
understanding systems-level anesthetic effects in humans. General anesthetic drugs dramatically reduce or 
increase (unique to ketamine) cerebral metabolism and blood flow globally across the brain.10-16 This is 
consistent with our understanding that general anesthetic drugs act at multiple sites throughout the brain.1,9 
Stimulus-induced activity in primary cortical areas decreases under anesthesia,16-20 as does functional 
connectivity,21-26 though some degree of resting state connectivity has been shown to persist.27,28 Ascending 
arousal systems spanning the brainstem, thalamic and cortical networks appear to become active during 
emergence from anesthesia-induced unconsciousness.29,30 Disruption of anterior-posterior cortico-cortical 
connectivity has been proposed as a common mechanism to explain these diverse findings.31-36 However, 
there is also considerable evidence to support thalamocortical12,20,26,30,37-39 and subcortical mechanisms as 
well.9  
 
The neurophysiological mechanisms underlying these observed changes in brain metabolism and 
functional connectivity remain unclear. However, anesthetic drugs are known to produce large stereotyped 
oscillations that may explain these brain metabolism and functional connectivity changes.30,38-44 To bridge the 
gap between observed changes in brain metabolism and fMRI-derived functional connectivity, it is essential to 
conduct studies that can simultaneously observe fast time-scale neurophysiological dynamics across multiple 
functionally-connected brain regions. To understand how neurophysiology relates to time-varying states of 
altered arousal requires detailed behavioral characterizations. Although it is clear that unresponsiveness is not 
necessarily unconsciousness,45 behavioral responses nonetheless provide crucial information on the state of 
altered arousal.46,47 Most of the aforementioned work has been performed in propofol or inhaled anesthetics, 
and  studies of ketamine are clearly needed. 
 
 
 
 
Ketamine 
Ketamine is an anesthetic, an anesthetic adjunct and an analgesic that acts primarily by binding to 
NMDA type glutamate receptors in the brain and spinal cord.9 Ketamine is a channel blocker and thus requires 
an open channel to be effective.48 Because the channels on inhibitory interneurons are generally more active 
than those on pyramidal neurons, ketamine primarily affects inhibitory interneurons at low to moderate doses 
(Fig. 1), leading typically to increased neural activity.49,50 This is why cerebral metabolism increases with low 
doses of ketamine. Hallucinations, dissociative states, euphoria and dysphoria are common with low dose 
ketamine because brain regions, such as the cortex, hippocampus and amygdala, continue to communicate 


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but with less modulation and control by inhibitory interneurons. Information is processed without proper 
coordination in space and time.1,9 This state is associated with high frequency beta-gamma (>30 Hz) 
oscillations.51 Analgesia results most likely from the action of ketamine on glutamate NMDA receptors at the 
dorsal root ganglia, the first synapse of the pain pathway in the spinal cord where glutamate is the primary 
neurotransmitter (Fig. 1).48  
 
We analyzed 4-channel frontal EEG recorded during routine monitoring in patients receiving ketamine 
(2mg/kg; n = 12 patients) to induce general anesthesia for surgery. As illustrated in figure 2 (middle panel), 
immediately after induction, we observed an alternating pattern of slow oscillations (0.1-4 Hz) and gamma 
bursts (30-40 Hz), Also illustrated in figure 2 (right most panel), this oscillatory dynamic eventually transitioned 
to persistent gamma oscillations (30-40 Hz) after several minutes. Both the slow-gamma and gamma patterns 
were associated with increased theta oscillations (4-8 Hz) and decreased beta/gamma oscillations (10-20 Hz).  
 
Unfortunately, this study and those from other research groups have not provided information on how 
the spatio-temporal dynamics of ketamine-induced oscillatory dynamics relate to loss of consciousness, return 
of consciousness or hallucinatory states. This is because ketamine has been administered in a bolus fashion in 
these studies. Ketamine-induced EEG dynamics may aid principled approaches to brain state monitoring and 
targeting during general anesthesia. They may also lend insights into anti-nociceptive or pain mechanisms. 
Additionally, parallels between ketamine-induced hallucinatory states and clinical diagnoses associated with 
hallucinatory states (i.e. schizophrenia) may lend mechanistic insights into abnormal brain functioning. 
 
Therefore, we aim to study the association between ketamine-induced neural oscillations, altered states 
of arousal and the perception of painful stimuli. Our central hypothesis is that ketamine-induced neural 
oscillations will exhibit clear distinctions between altered arousal states. Our study cohort will be comprised of 
healthy volunteers. We will perform assessments for hallucinations, anxiety and pain. At the conclusion of this 
study, we will have expanded our knowledge of the neurophysiology associated with ketamine-induced altered 
arousal states. The proposed human study is an integral component of our NIH P01 grant “Integrated Systems 
Neuroscience Studies of General Anesthesia (5 P01 GM118269) that is structured to study ketamine-induced 
neurophysiological dynamics across scales using recordings obtained from rodents and non-human primates, 
and from computational models derived from dynamical systems modeling. 
 
2. SPECIFIC AIMS 
AIM 1: To use high-density EEG recordings to characterize the different brain states induced by ketamine  
Hypothesis 1.1. Ketamine gamma-burst pattern will be associated with a zero probability of response to 
auditory stimuli  
Hypothesis 1.2.  Ketamine gamma-stable pattern consists of two distinct brain states: an anesthetic state with 
zero probability of response to auditory stimuli and a hallucinatory state with non-zero probability of response 
to auditory stimuli  
 
AIM 2: To use high-density EEG recordings to characterize oscillatory dynamics associated with the analgesic 
effect of ketamine 
Hypothesis 2.1. Ketamine theta power will correlate with analgesia 
Hypothesis 2.2.  Ketamine gamma power will not correlate with analgesia 
 
AIM 3: To use inflammatory profiling of serum to understand the effect of ketamine on systemic inflammation  
Hypothesis 3.1.  Ketamine-anesthesia will be associated with decreased levels of pro-inflammatory cytokines 
interleukin 6 and TNF-alpha 
Hypothesis 3.2.  Levels of pro-inflammatory cytokines interleukin 6 and TNF-alpha will correlate with a 
decrease in perception of painful stimuli 
 
3. SUBJECT SELECTION  
All study subjects will be American Society of Anesthesiologists (ASA) physical status classification P1. That is, 
all study subjects will be fit and healthy. A complete medical history will be taken and a complete physical 
examination will be given to rule out active and chronic medical problems.  


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Primary Inclusion Criteria: 
Between the ages of 18 to 45 
Normal body weight and habitus, BMI ≤ 30 
Non-smoker 
American Society of Anesthesiologists (ASA) physical status classification P1 
 
Primary Exclusion Criteria include but are not limited to: 
Cardiovascular: 
myocardial infarction, coronary artery disease, peripheral vascular disease, arrhythmia, 
congestive heart failure, valvular disease, hypertension 
Respiratory:  
bronchitis, chronic obstructive pulmonary disease, smoking, shortness of breath 
Hepatic: 
hepatitis, jaundice, ascites 
Neurologic: 
seizure, stroke, positive neurologic findings on neurologic examination, multiple 
sclerosis, Meniere’s disease, Parkinson’s disease, neuropathy, peripheral stenosis 
Gastrointestinal: 
esophageal reflux, hiatal hernia, ulcer 
Endocrine: 
diabetes, thyroid disease 
Renal: 
acute or chronic severe renal insufficiency  
Hematologic: 
blood dyscrasias, anemia, coagulopathies, on anticoagulant therapy 
Musculoskeletal: 
prior surgery or trauma to head neck or face, arthritis, personal or family history of 
malignant hyperthermia 
Psychiatric: 
history or treatment for an active psychiatric problem, depression 
Reproductive: 
pregnancy, breast-feeding 
Medications:  
regular use of prescription and non-prescription medications expected to affect CNS 
function, St. John’s Wort 
Allergies:  
labetalol, ondansetron, glycopyrrolate, ketamine, midazolam 
 
Patients will be excluded from our study if they fail to pass a drug test that screens for the following: 
Cocaine 
(COC), 
d-Amphetamine 
(AMP), 
d-Methamphetamine 
(Mamp), 
Tetrahydrocannabinol (THC), Methadone (MTD), Opiates (OPI), Phencyclidine 
(PCP), Barbiturates (BAR), Benzodiazepines (BZO), Oxycodone (OXY) 
 
 
Recruitment:  We will select 15 volunteer subjects (male and female) between the ages of 18-45 years.  
The subjects will be recruited using:                                                 
An announcement of the study distributed through the Partners Public Affairs distribution list.                 
The MGH Research Study Volunteer Program (RSVP).       
 
 
 
4. SUBJECT ENROLLMENT 
Procedure for informed consent: Prior to the study, each subject will sign informed consent (detailed in 
Screening Visit subsection of Study Design Section below). The investigator obtaining consent will explain in 
detail the protocol of the study, its purpose and potential benefits to society. Subjects will be informed that if 
they feel uncomfortable with the study, they can choose to terminate the study at any time.  
 
Treatment Assignment and Randomization: Not applicable 
                              
Retention: All subjects who provide verbal or written consent but later decline participation in the study will not 
be subject to any study-related follow-up. 
 
Remuneration: For successful completion of this protocol, subject remuneration will be $500. The subject will 
also be compensated for the cost of parking for their study visit. 
 


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Location:  These studies will take place on White 5 at the Carl Rosow Center for Clinical Research. White 5, 
which is located in the cardiac anesthesia office suite, was constructed specifically for the performance of 
research on human subjects receiving the depressant medications used in anesthesia. The research area is 
built to the same standard as a typical surgical procedure room at MGH with respect to ventilation, temperature 
control, plumbing and electrical facilities, as well as storage. There is piped oxygen and air, wall suction and 
waste anesthetic gas removal. The hospital’s backup generator supports electrical outlets in this location. 
There is a fully equipped anesthesia machine, standard anesthetic care monitors and a fully equipped code 
cart. The code cart and medications are checked at intervals by personnel from the OR pharmacy, and the 
anesthesia equipment is safety checked and maintained by Anesthesia Bioengineering. Research subjects 
receiving anesthetic drugs in this unit are given an identical standard of care as patients in MGH operating 
rooms.  
 
5. STUDY PROCEDURES 
Screening Visit: All subjects will complete a screening visit. Informed consent will be obtained during this 
study visit. Study subjects will undergo screening to ensure that they meet the basic inclusion/exclusion criteria 
for the study and give written informed consent. Study staff members will also ensure patients are enrolled in 
an appropriate insurance plan. Insurance coverage will be evaluated through medical record review. Each 
study subject will be asked to bring a copy of his/her insurance card to the screening visit. This is to ensure 
coverage in the unlikely event that follow-up medical care is necessary for an adverse event. All further 
questions will be explained as needed. A urine hCG pregnancy test and urine drug screen will be performed. 
Only subjects with negative tests will be enrolled. 
  
Subjects will be given a standard pre-anesthetic physical examination. Particular attention will be paid to the 
subject’s airway anatomy and neurologic function. Abnormal findings on physical examination may result in 
exclusion from the study. Abnormal findings will be reported to the subjects, and recommendations for medical 
follow-up will be given as needed. 
 
A complete blood count, blood glucose level, liver function tests (LFTs), blood urea nitrogen (BUN) and 
creatinine (Cr) level panel will be obtained at the initial screening visit. For inclusion into the study protocol, 
each subject will be required to have values within the range of normal with the following exceptions: (1) AST 
and ALT levels within 1.5 times the upper limit of normal; (2) Alkaline phosphatase ≤ 130; (3) WBC ≥ 3.5; (4) 
Platelet count ≥ 120; (5) BUN within 1.5 times the upper limit of normal; (6) red cell indices. A formal exception 
will be obtained from the IRB for values outside of this range that represent an expected variation (i.e. 
increased bilirubin in a patient with known Gilbert’s syndrome). Any subject who tests positive for any “street 
drugs” (amphetamine, barbiturates, benzodiazepines, cocaine, opiates, or phencyclidine) will be excluded from 
the study. Any subject who tests positive for cannabinoids may be excluded from the study if drug-abuse is 
suspected. A 12-lead EKG will be performed to confirm healthy cardiac functioning. 
 
Study Visit: During the study, a board-certified anesthesiologist will be present whose sole 
responsibility will be to monitor (check) your safety. The sequence of this study visit will be as follows: 
arrival (approximately 45 minutes), baseline (approximately 15 minutes), loss of consciousness (approximately 
15 minutes), recovery of consciousness (approximately 60 minutes), and discharge (approximately 45 
minutes). We anticipate the study to last approximately 3 to 5 hours.  
 
A. Arrival: Confirmation of the study subjects’ fasting status (minimum 8 hours) will be made. A urine sample 
will be obtained for pregnancy testing in all female study subjects. The following assessments will be 
performed: 1.) Clinician Administered Dissociative States Scale (CADSS)52 to assess for hallucinations; 2.) 
Promis Item Bank v.1.0 – Emotional Distress-Anxiety Short Form 8A modified to ask for symptoms 
experienced within the past hour; 3.) Promis Item Bank v.1.0 – Meaning and purpose Short Form 8A; and, 4.) 
Promis Item Bank v.1.0 – Positive Affect Short Form 15A (modified to ask for symptoms experienced within the 
past hour). The following computer presented neurocognitive assessment tests will also be performed: Global 
Precedence, Operation Span and Columbia Card tasks will also be administered (https://www.neurobs.com). 
 


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Standard monitors for anesthesia care monitoring including blood pressure (cuff), electrocardiogram, 
capnography and pulse oximetry and a 64-channel EEG montage will be placed on the subject. Video of the 
study subject may be recorded during baseline, induction and recovery from hypnosis periods to assess the 
study subject’s level of arousal. Permission to record video for data analysis purposes will be obtained from the 
research consent form. An intravenous line will be placed for drug administration, and we will obtain 
approximately 15ml of blood (baseline pre-ketamine). 
 
During this period, a calibrated cuff pain stimuli will be delivered to the gastrocnemius area of the lower leg 
using a validated cuff pain device (Hokanson Rapid Cuff Inflator),53-56 titrated to 8-9/10 pain. One advantage of 
using cuff algometry pain is that, unlike more superficial methods (e.g. heat pain), cuff pain responses are 
unaffected by sensitization or desensitization of the skin.53  The following questionnaires will be administered to 
assess pain intensity and quality: 1) PROMIS Numeric Rating Scale V1.0 – Pain Intensity 1A; 2) PROMIS 
Scale v2.0 – Neuropathic Pain Quality 5a; and, 3) PROMIS Scale v2.0 – Nociceptive Pain Quality 5a. 
Participants will be oriented to the following pain scale: (1) 0-1 out of 10 as “tolerable”; (2) 2-3 out of 10 as 
“slight discomfort”; (3) 4-7 out of 10 as “moderate discomfort”; (4) 8-9 out of 10 as “painful”; and (5) 10 as 
“maximum pain”. 
 
B. Baseline: A 10 to 15-minute period of EEG recording will be obtained for EEG calibration (i.e. eye 
movements, eye blinks, facial muscle movement) and EEG normalization (awake-eyes closed). Recordings of 
physiological measurements (blood pressure, heart rate, pulse oximetry, end-tidal carbon dioxide, 
electrooculogram, electromyogram and galvanic skin response) will be initiated and maintained from the 
beginning of the study protocol until the subject is ready for discharge.  
 
C. Loss consciousness: 2mg/kg of ketamine will be infused (Medfusion pump) over approximately 5 minutes 
to gradually induce and allow for rapid emergence from ketamine-anesthesia. This anesthetic dose is expected 
to cause approximately 10-15 minutes of loss of consciousness/responsiveness. Subjects will be asked to 
respond to auditory stimuli via button-press jittered at random between 4 and 8 second intervals in order to 
resolve the precise period at which loss and recovery of consciousness/responsiveness occurred at a fine 
temporal scale.  
 
General anesthetic agents, including ketamine, can produce apnea after loss of consciousness. The standard 
clinical approach for airway management in surgical patients is for the anesthesiologist to assist oxygenation 
and ventilation after the loss of consciousness. Thus, a staff anesthesiologist will use standard airway 
maneuvers to maintain normal oxygenation and ventilation. These maneuvers include a jaw and chin thrust 
and assisted ventilation with a mask and bag as part of a circle circuit. Ventilation will be manually assisted as 
needed. At all times, the inspired oxygen concentration, expired carbon dioxide waveform and partial pressure 
will be monitored continuously. The minimum inspired oxygen concentration will be 30%. The end-tidal 
(capnogram) carbon dioxide levels will be maintained within 10% of the baseline values. Manually assisted 
oxygenation and ventilation will continue until the subject recovers spontaneous ventilation. Vlisides et al. 
recently studied correlates of ketamine-anesthesia.57 Because the authors rapidly administered 1.5mg/kg bolus 
of ketamine, the temporal correlation of EEG dynamics with loss of consciousness was not feasible in this 
study. Also, this study did not relate ketamine-induced altered arousal states to pain perception. While planning 
the present study, we spoke with the study authors and confirmed that spontaneous ventilation was maintained 
in all of their study subjects. They noted that nausea was frequently encountered in their study cohort. Thus, 
we expect that spontaneous ventilation will be maintained in our study subjects. Prior to the administration of 
ketamine, we will administer 4mg intravenous odansetron for the pre-emptive treatment of nausea.  
 
Research staff will be responsible for monitoring potential side effects. An experienced board-certified 
anesthesiologist will always monitor and care for the subject according to the standards for delivery of 
anesthesia at MGH. The White 5 research unit is equipped with an anesthesia machine and physiologic data 
are collected electronically. This research unit has been specifically designed and equipped according to MGH 
standards and Massachusetts regulations as an anesthetizing location, and it has been approved for this 
purpose by the Clinical Practices and Safety Committee of the MGH Department of Anesthesia, Critical Care 
and Pain Medicine. Because ketamine may cause an increase in the heart rate and blood pressure, an 


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anesthesiologist may be required to administer intravenous labetalol 5 to 20 mg IV push over approximately 2 
minutes for three blood pressure readings greater than 160/100. Blood pressure readings will be obtained 3-5 
minutes apart. Intravenous glycopyrrolate in 0.1mg increments may also be administered for excessive salivary 
secretion. In order to minimize external stimuli, ketamine administration will occur in a room with low lighting 
and minimal noise. Based on the acuity of physiological or behavioral changes, the anesthesiologist may 
modify these treatment recommendations.  
 
The study investigator will be available over the phone at anytime to address any concerns. Subjects will be 
advised to contact the study PI for any medical related concerns. The study PI may advise subjects to obtain 
follow-up care from their nearest emergency department or primary care physician. Study staff will use the 
EPIC alert system to monitor subject admittance to any Partners Hospital. The study investigator will contact all 
study subjects 24 hours after completion of the study visit to address any concerns or study related adverse 
effects.  
 
D. Recovery of consciousness: We will conduct assessments 5-minutes after recovery of consciousness 
and at approximately 15-minute intervals after recovery of consciousness for a total of three assessments. 
These assessments will consist of: 1.) CADSS; 2.) Promis Item Bank v.1.0 – Emotional Distress-Anxiety Short 
Form 8A modified to ask for symptoms experienced within the past hour; 3.) Promis Item Bank v.1.0 – Meaning 
and Purpose Short Form 8A; and, 4.) Promis Item Bank v.1.0 – Positive Affect Short Form 15A (modified to 
ask for symptoms experienced within the past hour. After these assessments, the cuff pain device will be 
inflated (pre-calibrated pressure; see Arrival subsection above), and pain intensity and quality assessments will 
consist of: 1.) PROMIS Numeric Rating Scale V1.0 – Pain Intensity 1A; 2.) PROMIS Scale v2.0 – Neuropathic 
Pain Quality 5a; and, 3.) PROMIS Scale v2.0 – Nociceptive Pain Quality 5a.  
 
 
After the third assessment (i.e. approximately 35 minutes after recovery of consciousness), we will administer 
0.05 mg/kg of midazolam (maximum dose of 4 mg) to resolve ketamine-induced perceptual disturbances. 
Midazolam is routinely administered during the peri-operative period to mitigate ketamine-induced perceptual 
disturbances. Approximately 5 minutes after midazolam is administered, we will resume assessments for a 
minimum of two assessments (approximately 55 minutes after recovery of consciousness) or until the subject 
is ready for discharge.  We will obtain approximately 15ml of blood (post-ketamine, pre-midazolam). The 
following computer presented neurocognitive assessment tests will also be performed: Global Precedence, 
Operation Span and Columbia Card tasks will also be administered (post-ketamine, pre-midazolam). 
 
 
E. Discharge: If medically stable, as deemed by a board-certified anesthesiologist, the intravenous line and 
physiological monitoring devices will be discontinued, and subjects will be discharged home with a responsible 
family member or other adult caretaker. Discharge home will be based on criteria established by the MGH 
Department of Anesthesia practices for discharge from the hospital following ambulatory surgery. The subject 
must have stable vital signs, be able to respond appropriately to normal commands, be pain free, be free from 
any nausea and vomiting and have no bleeding from the intravenous sites. Subjects must be able to walk 
unassisted and have an accompanying adult to escort them home. Subjects will be advised against returning 
to work and driving or operating heavy equipment for 24 hours.  
 
If subjects experience adverse events at home, they will be referred for evaluation at the nearest emergency 
department. These instructions will also be provided to the responsible adult escort prior to discharge. The 
subject’s individual insurance plan will be responsible for covering this visit.  
 
 
 
6. BIOSTATISTICAL ANALYSIS 
EEG acquisition Preprocessing: Continuous 64-channel EEG will be recorded. All data will be stored for 
subsequent off-line analysis. We will apply an anti-aliasing filter and down-sample the EEG data to reduce 
computational complexity before analysis. Bandpass filtering of the acquired signal will vary depending upon 


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the features of the EEG data of interest. Trigger signals will be sent from the stimulus delivery system to the 
EEG recording system to tag the stimulus events for subsequent binning, temporal epoching and averaging of 
EEG data into the relevant evoked potential averages.  
 
Spectral Analysis: We will compute spectrograms for all subjects using the multitaper method. We will also 
compute group-level baseline-normalized spectrograms for induction and emergence by taking the median 
across subjects with the data aligned to the LOC and ROC time points, respectively. To assess statistical 
significance for the difference in EEG spectra at each frequency, we will compute the 99% confidence interval 
of the median difference between groups by using an empirical bootstrap approach. The null hypothesis will be 
rejected only if the confidence interval of the median difference at each frequency exceeds the significance 
threshold over a contiguous frequency range ≥ 2W. 
 
Eigenvalue and Modal Projection Analyses: We will perform an eigenvector decomposition analysis of the 
cross-spectral matrix to identify the principal modes of oscillation in the conscious and unconscious states and 
to analyze how activity within these principal modes changes through time. We will estimate the cross-spectral 
matrices Pbaseline(f) and Punconscious(f) at each frequency f using the multitaper method using data from the full 
baseline period, as well as segments of at least 5 min extending from LOC to ROC, respectively, for each 
subject. An eigenvalue decomposition of the median cross-spectral matrix at each frequency will be performed. 
Each eigenvector describes a coherent spatial distribution or mode of oscillation, and the corresponding 
eigenvalue quantifies the power in this mode. We then use modal projection analysis to characterize how 
power within principal modes change as a function of time. A permutation-based procedure will be performed 
to assess statistical significance for the modal projection analysis.  
 
Behavioral Analysis: The probability of response to verbal stimuli and the difference in probability of response 
will be estimated by using Bayesian Monte Carlo methods to fit a state-space model to these data. To perform 
group-level analyses, we will align the behavioral data across subjects with respect to each subject’s LOC time 
for induction and with respect to each subject’s ROC time for emergence. We will then pool the responses, and 
pooled data will be used to estimate group-level probabilities of response using the state-space model. 
 
Inflammatory profile Analysis: Plasma samples will be submitted to Myriad/Rules Based Medicine (Myriad 
RBM, Austin, TX, USA) for analysis using their proprietary platform. Wilcoxon rank-sum tests with corrections 
for multiple comparisons will be used to assess analyte differences. In exploratory analyses, we will examine 
Pearson correlations between analytes and variables of interest (i.e. pain, anxiety).  
 
Power Analysis: Assuming the point estimate for gamma power at baseline is -20 dB and 5 dB for ketamine 
induced-unconsciousness (Fig 2.), a standard deviation of 20 dB, type 1 error of 0.05, and desired power of 
0.9, n =14 study volunteers will enable us to detect a gamma power ratio of 25 dB. Therefore, we aim to recruit 
up to 15 subjects.   
 
7. RISKS AND DISCOMFORTS 
EEG risks: The risks associated with EEG electrodes are redness and irritation at the placement site. 
 
Questionnaire risks: Minimal risks associated with completing questionnaires are subject fatigue and the 
possibility of minor psychological distress associated with answering sensitive questions regarding 
psychological functioning. 
 
Data risks: Procedures are in place to reduce the likelihood of a breach of confidentiality including the de-
identification of data and storage of data only on Partners approved devices/portals. However, there is a small 
risk that people outside of this study may be exposed to information about study subjects. 
 
Ketamine: Although it has a good safety profile overall, ketamine has documented sympathomimetic activity 
that may result in mild to moderate increases in heart rate, blood pressure and cardiac output, though this 
activity is generally short-lived.58 Other possible side effects reported during ketamine infusion include 
arrhythmia, increased salivation, increased bronchial secretions, horizontal nystagmus, euphoria and 


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hallucinations. Nystagmus may persist for a period after the ketamine infusion has terminated. Any acute 
changes in physiology, such as changes in heart rate or blood pressure, will be treated using standard 
anesthesiology practices. Rare side effects are allergic reactions (skin rash), pain at the site of injection, 
increased intraocular pressure, ulcerations and inflammation in the bladder (reported in ketamine abusers). 
Ketamine is a controlled substance and has the potential for abuse and dependence, particularly in subjects 
with history of drug abuse. Subjects with history of substance abuse or dependence will be excluded.  
 
Glycopyrrolate risks: Risks involved in the administration of glycopyrrolate include hypertension and 
tachyycardia. 
 
Labetalol risks: Risks involved in the administration of labetalol include hypotension and bradycardia. 
 
Cuff pain stimuli risks: Risks of cuff pain include mild transient bruising associated with inflation of the cuff. 
Our previous experience has also demonstrated that pain ratings go down to nil within several seconds of 
stimulus termination. A button press rapidly deflates the cuff, ensuring subject safety. 
 
Blood draw risks: Pain at the needle insertion site, infection, and bleeding. 
 
 
8. POTENTIAL BENEFITS 
Subjects will have no direct benefit from taking part in this study. Ketamine-induced EEG dynamics may aid 
principled approaches to brain state monitoring and targeting during general anesthesia. They may also lend 
insights into anti-nociceptive or pain mechanisms. 
 
9. MONITORING AND QUALITY ASSURANCE 
The principal investigator and co-investigators will be responsible for monitoring and quality assurance of the 
study. In conjunction with the research assistants, weekly meetings will be held and documented. Current 
subjects in the study will be discussed at each meeting, and charts will be reviewed for completeness. The 
team will evaluate the progress of the study; verify that the rights and well being of the subjects are protected; 
ensure that the reported study data are accurate, complete and verifiable from source documents; and assure 
the conduct of the study is in compliance with the approved protocol and amendments. 
 
Serious Adverse Events:  Expedited review will occur for all events meeting the FDA definition of SAEs – i.e., 
any events that are fatal, immediately life-threatening, permanently or substantially disabling, or 
requiring/prolonging inpatient hospitalization. This also includes any event that a study investigator judges to 
impose a significant hazard, contraindication, side effect or precaution.  Reporting to the IRB will be done 
within 24 hours of the SAE. 
 
Study Stopping Rules:  If at any time during the course of the study the PIs or CO-Is judge that risk to 
subjects outweighs the potential benefits, the PI/CO-Is shall have the discretion and responsibility to 
recommend that the study  terminated.  
  
AE Reporting Guidelines: Unanticipated problems involving risks to subjects or others including adverse 
events will be reported to the PHRC in accordance with PHRC unanticipated problems including adverse 
events reporting guidelines, as well as the RDRC within 5 days. 
 
 


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10. REFERENCES 
1. 
Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med 2010;363:2638-50. 
2. 
Franks NP, Lieb WR. Mechanisms of general anesthesia. Environ Health Perspect 1990;87:199-205. 
3. 
Franks NP, Lieb WR. Do general anaesthetics act by competitive binding to specific receptors? Nature 
1984;310:599-601. 
4. 
Rudolph U, Antkowiak B. Molecular and neuronal substrates for general anaesthetics. Nat Rev 
Neurosci 2004;5:709-20. 
5. 
Hemmings HC, Jr., Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular 
mechanisms of general anesthetic action. Trends Pharmacol Sci 2005;26:503-10. 
6. 
Eckenhoff RG. Promiscuous ligands and attractive cavities: how do the inhaled anesthetics work? Mol 
Interv 2001;1:258-68. 
7. 
Eckenhoff RG. Why can all of biology be anesthetized? Anesth Analg 2008;107:859-61. 
8. 
Shafer S, Flood P, Schwinn D. Basic Principles of Pharmacology, In: Miller's Anesthesia, RD Miller, LI 
Eriksson, LA Fleisher, JP Wiener-Kronish, WL Young. Philadelphia: Churchhill Livingston; 2009. 
9. 
Brown EN, Purdon PL, Van Dort CJ. General anesthesia and altered states of arousal: a systems 
neuroscience analysis. Annu Rev Neurosci 2011;34:601-28. 
10. 
Alkire MT, Haier RJ, Barker SJ, Shah NK, Wu JC, Kao YJ. Cerebral metabolism during propofol 
anesthesia in humans studied with positron emission tomography. Anesthesiology 1995;82:393-403. 
11. 
Veselis RA, Reinsel RA, Beattie BJ, et al. Midazolam changes cerebral blood flow in discrete brain 
regions: an H2(15)O positron emission tomography study. Anesthesiology 1997;87:1106-17. 
12. 
Fiset P, Paus T, Daloze T, et al. Brain mechanisms of propofol-induced loss of consciousness in 
humans: a positron emission tomographic study. JNeurosci 1999;19:5506-13. 
13. 
Bonhomme V, Fiset P, Meuret P, et al. Propofol Anesthesia and Cerebral Blood Flow Changes Elicited 
by Vibrotactile Stimulation: A Positron Emission Tomography Study. JNeurophysiol 2001;85:1299-308. 
14. 
Antognini JF, Buonocore MH, Disbrow EA, Carstens E. Isoflurane anesthesia blunts cerebral 
responses to noxious and innocuous stimuli: a fMRI study. Life Sci 1997;61:L-54. 
15. 
Kerssens C, Hamann S, Peltier S, Hu XP, Byas-Smith MG, Sebel PS. Attenuated brain response to 
auditory word stimulation with sevoflurane: a functional magnetic resonance imaging study in humans. 
Anesthesiology 2005;103:11-9. 
16. 
Mhuircheartaigh NR, Warnaby C, Rogers R, Jbabdi S, Tracey I. Slow-wave activity saturation and 
thalamocortical isolation during propofol anesthesia in humans. Sci Transl Med 2013;5:208ra148. 
17. 
Mhuircheartaigh RN, Rosenorn-Lanng D, Wise R, Jbabdi S, Rogers R, Tracey I. Cortical and 
subcortical connectivity changes during decreasing levels of consciousness in humans: a functional magnetic 
resonance imaging study using propofol. J Neurosci 2010;30:9095-102. 
18. 
Monti MM, Lutkenhoff ES, Rubinov M, et al. Dynamic change of global and local information processing 
in propofol-induced loss and recovery of consciousness. PLoS Comput Biol 2013;9:e1003271. 


Version: 05/11/2018 
 
11
19. 
Purdon PL, Pierce ET, Bonmassar G, et al. Simultaneous electroencephalography and functional 
magnetic resonance imaging of general anesthesia. Ann N Y Acad Sci 2009;1157:61-70. 
20. 
Guldenmund P, Demertzi A, Boveroux P, et al. Thalamus, brainstem and salience network connectivity 
changes during propofol-induced sedation and unconsciousness. Brain Connect 2013;3:273-85. 
21. 
Gomez F, Phillips C, Soddu A, et al. Changes in effective connectivity by propofol sedation. PLoS One 
2013;8:e71370. 
22. 
Casali AG, Gosseries O, Rosanova M, et al. A theoretically based index of consciousness independent 
of sensory processing and behavior. Sci Transl Med 2013;5:198ra05. 
23. 
Schrouff J, Perlbarg V, Boly M, et al. Brain functional integration decreases during propofol-induced 
loss of consciousness. Neuroimage 2011;57:198-205. 
24. 
Boveroux P, Vanhaudenhuyse A, Bruno MA, et al. Breakdown of within- and between-network resting 
state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. 
Anesthesiology 2010;113:1038-53. 
25. 
Alkire MT, Haier RJ, Fallon JH. Toward a unified theory of narcosis: brain imaging evidence for a 
thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. ConsciousCogn 
2000;9:370-86. 
26. 
Alkire MT, Pomfrett CJ, Haier RJ, et al. Functional brain imaging during anesthesia in humans: effects 
of halothane on global and regional cerebral glucose metabolism. Anesthesiology 1999;90:701-9. 
27. 
Alkire MT, Haier RJ, Shah NK, Anderson CT. Positron emission tomography study of regional cerebral 
metabolism in humans during isoflurane anesthesia. Anesthesiology 1997;86:549-57. 
28. 
Breshears JD, Roland JL, Sharma M, et al. Stable and dynamic cortical electrophysiology of induction 
and emergence with propofol anesthesia. Proc Natl Acad Sci U S A 2010;107:21170-5. 
29. 
Langsjo JW, Alkire MT, Kaskinoro K, et al. Returning from oblivion: imaging the neural core of 
consciousness. J Neurosci 2012;32:4935-43. 
30. 
Liu X, Lauer KK, Ward BD, Li SJ, Hudetz AG. Differential effects of deep sedation with propofol on the 
specific and nonspecific thalamocortical systems: a functional magnetic resonance imaging study. 
Anesthesiology 2013;118:59-69. 
31. 
Hudetz AG. General anesthesia and human brain connectivity. Brain Connect 2012;2:291-302. 
32. 
Vincent JL, Patel GH, Fox MD, et al. Intrinsic functional architecture in the anaesthetized monkey brain. 
Nature 2007;447:83-6. 
33. 
Ku SW, Lee U, Noh GJ, Jun IG, Mashour GA. Preferential inhibition of frontal-to-parietal feedback 
connectivity is a neurophysiologic correlate of general anesthesia in surgical patients. PLoS One 
2011;6:e25155. 
34. 
Lee H, Mashour GA, Noh GJ, Kim S, Lee U. Reconfiguration of Network Hub Structure after Propofol-
induced Unconsciousness. Anesthesiology 2013. 
35. 
Lee U, Ku S, Noh G, Baek S, Choi B, Mashour GA. Disruption of frontal-parietal communication by 
ketamine, propofol, and sevoflurane. Anesthesiology 2013;118:1264-75. 


Version: 05/11/2018 
 
12
36. 
Shin J, Mashour GA, Ku S, Kim S, Lee U. Subgraph "backbone" analysis of dynamic brain networks 
during consciousness and anesthesia. PLoS One 2013;8:e70899. 
37. 
Herdman AT, Lins O, Van Roon P, Stapells DR, Scherg M, Picton TW. Intracerebral sources of human 
auditory steady-state responses. Brain Topogr 2002;15:69-86. 
38. 
Cimenser A, Purdon PL, Pierce ET, et al. Tracking brain states under general anesthesia by using 
global coherence analysis. Proc Natl Acad Sci U S A 2011;108:8832-7. 
39. 
Purdon PL, Pierce ET, Mukamel EA, et al. Electroencephalogram signatures of loss and recovery of 
consciousness from propofol. Proceedings of the National Academy of Sciences of the United States of 
America 2013;110:E1142-51. 
40. 
Gugino LD, Chabot RJ, Prichep LS, John ER, Formanek V, Aglio LS. Quantitative EEG changes 
associated with loss and return of consciousness in healthy adult volunteers anaesthetized with propofol or 
sevoflurane. British journal of anaesthesia 2001;87:421-8. 
41. 
Feshchenko VA, Veselis RA, Reinsel RA. Propofol-induced alpha rhythm. Neuropsychobiology 
2004;50:257-66. 
42. 
Gibbs FA, Gibbs EL, Lennox WG. Effect on the electroencephalogram of certain drugs which influence 
nervous activity. Arch Intern Med 1937;60:154-69. 
43. 
Velly LJ, Rey MF, Bruder NJ, et al. Differential dynamic of action on cortical and subcortical structures 
of anesthetic agents during induction of anesthesia. Anesthesiology 2007;107:202-12. 
44. 
Supp GG, Siegel M, Hipp JF, Engel AK. Cortical hypersynchrony predicts breakdown of sensory 
processing during loss of consciousness. Current biology : CB 2011;21:1988-93. 
45. 
Hanrahan SJ, Greger B, Parker RA, et al. The effects of propofol on local field potential spectra, action 
potential firing rate, and their temporal relationship in humans and felines. Front Hum Neurosci 2013;7:136. 
46. 
Mukamel EA, Pirondini E, Babadi B, et al. A transition in brain state during propofol induced 
unconsciousness. J Neurosci 2014;34:839-45. 
47. 
Sanders RD, Tononi G, Laureys S, Sleigh JW. Unresponsiveness not equal unconsciousness. 
Anesthesiology 2012;116:946-59. 
48. 
Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol 2008:313-33. 
49. 
Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 
1995;52:998-1007. 
50. 
Seamans J. Losing inhibition with ketamine. Nat Chem Biol 2008;4:91-3. 
51. 
Tsuda N, Hayashi K, Hagihira S, Sawa T. Ketamine, an NMDA-antagonist, increases the oscillatory 
frequencies of alpha-peaks on the electroencephalographic power spectrum. Acta Anaesthesiol Scand 
2007;51:472-81. 
52. 
Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the Clinician-
Administered Dissociative States Scale (CADSS). Journal of traumatic stress 1998;11:125-36. 
53. 
Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Computer-controlled pneumatic pressure algometry-
-a new technique for quantitative sensory testing. Eur J Pain 2001;5:267-77. 


Version: 05/11/2018 
 
13
54. 
Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Pressure-pain function in desensitized and 
hypersensitized muscle and skin assessed by cuff algometry. J Pain 2002;3:28-37. 
55. 
Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Spatial and temporal aspects of deep tissue pain 
assessed by cuff algometry. Pain 2002;100:19-26. 
56. 
Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Modality-specific facilitation and adaptation to painful 
tonic stimulation in humans. Eur J Pain 2002;6:475-84. 
57. 
Vlisides PE, Bel-Bahar T, Lee U, et al. Neurophysiologic Correlates of Ketamine Sedation and 
Anesthesia: A High-density Electroencephalography Study in Healthy Volunteers. Anesthesiology 
2017;127:58-69. 
58. 
Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. 
Ann Emerg Med 1990;19:1033-46. 
 

ICF_000.pdf: 
Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 1 of 14
Subject Identification
Protocol Title: Electroencephalogram Studies of Induction and Recovery 
from Ketamine-Induced General Anesthesia
Principal Investigator: Oluwaseun Johnson-Akeju, M.D., M.M.Sc
Site Principal Investigator:      
Description of Subject Population: 15 healthy male and female subjects, ages 
18-45 years. American Society of Anesthesiologists (ASA) physical status 
classification P1. 
About this consent form
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.”
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time.
Why is this research study being done?
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 2 of 14
Subject Identification
We are doing this research study to find out how and where ketamine acts in the brain.   Ketamine 
is an anesthetic (a drug or agent used to decrease or eliminate the feeling of pain by putting you in 
an unconscious state). 
We will look at your brain using a machine that records your brain’s electrical activity, called an 
electroencephalogram (EEG). EEG is a routine test done at the hospital.
The U.S. Food and Drug Administration (FDA) has approved ketamine for general anesthesia (loss 
of consciousness) before and during surgery. During this research study, you will receive ketamine 
at a high enough dose to induce general anesthesia (make you “fall asleep”).  We are asking you 
to take part because you are a healthy adult and are not currently taking medicines that affect brain 
function. We expect to enroll 15 people in this research study at Massachusetts General Hospital 
(MGH).
Conflict of Interest Disclosure
Dr. Johnson-Akeju, an  investigator on this study, is an inventor of technology that is used in this 
study. The hospital owns this technology and therefore Dr. Johnson-Akeju and the hospital may 
benefit financially if this study shows that the technology is valuable. The hospital’s 
conflict of interest policies are handled by the hospital’s owner, Partners HealthCare. In 
accordance with these policies, Partners has determined that the interests create no significant risk 
to the welfare of participants in this study or to the integrity of the research. If you want more 
information about this, please contact the Partners Office for Interactions with Industry at 857-
282-2024.
How long will I take part in this research study?
It will take you up to 2 weeks to complete this research study.  During this time, we will ask you 
to make 2 visits to the MGH.  The first visit will last approximately 3 to 5 hours while the second 
visit will last approximately 3 hours. The visits will take place at the MGH main campus.
What will happen in this research study?
If you choose to take part in this study, we will ask you to sign this consent form before we do any 
study procedures.
Study Visit 1 – Screening 
The Screening Visit will take about 3 to 5 hours.  This visit will take place at the MGH main 
campus. 
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 3 of 14
Subject Identification
During this visit, we will ask you some questions and do some tests to see if you qualify to take 
part in this research study.  The study doctor will review the results of these questions, tests, and 
procedures.  If you do not qualify, the study doctor will tell you why.  
At this visit, we will:

Ask about your medical history

Give you some questionnaires to fill out about your general health and well-being

Give you a physical exam, including measuring your height, weight, and vital signs 

Test your urine for drugs 

Draw a blood sample (about 4 tablespoons) for routine laboratory tests, if no recent tests 
performed at a Partners affiliated institution are available

Test your urine for pregnancy, if you are a female able to become pregnant. Pregnant 
women cannot take part in this study. 

Do an ECG (electrocardiogram). This test checks the electrical activity of your heart.  We 
will place several small, sticky pads on your chest, arms, and legs.  Each pad has a wire 
attached.  The wires connect to a machine that makes a recording of your heart rhythm.  
This painless test takes about 15 minutes.  

Please bring a copy of your insurance card to the screening visit for verification of health 
insurance coverage.
Urine Drug Screen
During this study, we will test your urine for certain drugs, including illegal drugs, such as cocaine 
and marijuana.  If your urine shows you have taken any of these drugs, you can’t be in this study.  
The results of the urine drug test will not become part of your medical record.  These test results 
will, however, remain part of your study record.  
Study Visit 2– EEG with ketamine
For safety reasons, you must have nothing to eat or drink for 8 hours before the study visit. 
This visit will take about 3 hours to complete and will take place at the Carl Rosow Center for 
Clinical Research on White 5 at the MGH Main Campus. 
If you are a female we will conduct another urine pregnancy test prior to the administration of 
ketamine. 
Up to 256 EEG electrodes will be placed on your head using a special hat (“EEG cap”). This will 
not require us to remove any of your hair. A small amount of EEG paste will be applied to each 
electrode and directly to the skin of your scalp to improve contact with your skin.  
We will place the following monitors on you:  
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 4 of 14
Subject Identification

Heart monitor

Blood pressure cuff

Oxygen saturation monitor (plastic device that is put on  your finger to measure the 
amount of oxygen in your blood) 

Skin conductance (how well your skin conducts electricity) will be measured with 
sensors placed on your fingers.  

Breathing volume (amount of air that is moved in and out of your lungs) will be 
measured using belts that are placed around your chest and abdomen (belly). 

Large cuff, similar to the blood pressure cuff, will be placed around your leg to produce a 
painful feeling (pain stimuli cuff). 
You will have an IV catheter (small, flexible tube) placed in an arm vein.  The IV catheter will be 
used to give you fluids or medications. 
During the study, a board-certified anesthesiologist will be present whose sole responsibility will 
be to monitor your safety. 
Ketamine will be given to you over the course of 5 minutes so that you will become drowsy and 
go under general anesthesia. This phase of the study will last for about 15-20 minutes. We will 
record your vital signs and brain waves (EEG) the entire time.  We may administer a medication 
called glycopyrrolate if ketamine causes you to produce excessive saliva. We may also administer 
a medication called labetalol if ketamine causes high blood pressure.
During the baseline period, about 10-15 minutes before we start giving you ketamine and while 
you are getting it, we will present you with an auditory stimulus.  During this time, you will listen 
to a series of “clicks” through a set of headphones placed in your ears. These clicks will be used 
to measure how your hearing functions while you are under anesthesia. 
Next, you will hear a command to click a mouse. Your response to this command will help us 
determine whether or not you are under anesthesia. This overall pattern of clicks and verbal 
command sounds will be repeated many times.  Before you are under anesthesia, we will practice 
this together until you become familiar and comfortable with the task. When you wake up and 
become aware of these sounds, you should continue performing the task.
During the baseline period and while you are waking up, we may inflate (blow up with air) the 
cuff on your leg to produce a painful feeling. This cuff is attached to a machine that controls the 
pressure of the air that will inflate the cuff. The pressure from this cuff is controlled and will be at 
a safe and tolerable range. The air pressure in the cuff will be increased for a period of time to 
cause slight discomfort. The pain should go away within several seconds after the cuff is deflated. 
Each individual experience of brief pain is called a pain stimulus. During the cuff calibration 
period, as well as throughout the study visit, you will be asked to rate your pain on a scale of 1 to 
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 5 of 14
Subject Identification
10. The following pain scale will be used to evaluate your pain: (1) 0-1 out of 10 as “tolerable”; 
(2) 2-3 out of 10 as “slight discomfort”; (3) 4-7 out of 10 as “moderate discomfort”; (4) 8-9 out of 
10 as “painful”; and (5) 10 as “maximum pain.”
While you are receiving the study drug, we may also begin an audio and video recording. The 
purpose of these recordings will be to relate your physical behavior to changes in your heart rate, 
blood pressure, breathing pattern, and oxygen intake during the transition to and from general 
anesthesia. 
After you wake up, you will be asked to answer some questions to assess your thinking and 
wakefulness. These questions will be administered twice, 30 minutes apart, after which you will 
be given a dose of midazolam. Midazolam will be used to stop hallucinations that may be caused 
by ketamine during your recovery period. The dose of midazolam is similar to the dose doctors 
prescribe to relieve mild anxiety. You will be asked some final questions to evaluate your 
wakefulness and thinking for approximately 30 minutes.
After the study procedure is complete, you will recover and rest for 1-2 hours. We will remove 
the EEG electrodes at this time. During this time, we will monitor you to make sure that the 
effects of ketamine have worn off enough for you to go home. 
You must have a responsible adult available to escort you home when you have completed 
the study. This responsible adult must be present regardless of the mode of transportation you 
choose, (for example, even if you take a cab or the bus). You cannot drive a motor vehicle, 
operate heavy machinery, drink alcohol, take any narcotic medications or medications that can 
cause drowsiness, or take part in any activity that requires alertness until 24 hours after you 
received the study drug. Additionally, we recommend that you consider taking the following day 
off, or at least refrain from driving, as some discomfort would not be unusual the following day. 
Time off work will not be considered an injury, and thus will not be covered by the study.
Use of the Audio or Video Recordings
Parts of the study will have educational and scientific value.  Therefore, we may want to use the 
video for teaching purposes, presentations at medical/scientific meeting, or publications in a 
medical/scientific journal. In some cases, it may be necessary to show your face as part of the 
video presentation. You may request to review the video before you leave. If you are 
uncomfortable with the video recording, you may also ask that the video be never shown for 
teaching purposes, presentations at medical/scientific meeting, or publications in a 
medical/scientific journal.
I give the Investigators permission to use my video information for the purposes research only and 
the video won’t be shown to others. ___________ (Subject Initials)
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 6 of 14
Subject Identification
-OR-
I give the Investigators permission to use my video information for the purposes of research, 
teaching, medical/scientific presentations and/or publications. 
___________ (Subject Initials)
Stopping the Study Early
You may stop taking part in the study for any reason. 
Also, the study doctor may take you out of the study without your permission.  This may happen 
because:

The study doctor thinks it is best for you to stop taking the study drug

You can’t make the required study visits

We stop doing the study for other reasons
If this happens, the study doctor will explain why you need to stop taking part in the study.  
If you should experience any concerning side effects following discharge (i.e. difficulty breathing, 
fevers, chest pain) please call 911 or proceed immediately to the nearest emergency room for 
evaluation. A study doctor will be available over the phone 24/7 to address any concerns. Please 
contact study doctors in the event of any post-discharge concerns (i.e. bruising at the IV site, 
tiredness, difficulty sleeping). MGH has an electronic system that lets your study doctors know if 
you are admitted to a Partners Hospital, or if you visit a Partners Hospital Emergency Department 
for any reason.  This alert will let the study doctors know why you are there.  We want to make 
sure the study doctors know about any possible problems or side effects you experience while you 
are taking part in the study.
What are the risks and possible discomforts from being in this research study?
Risks of Ketamine
Once enough ketamine has been given so that you are under general anesthesia, you may stop 
breathing on your own. This is an expected response to the ketamine. If this happens, the 
anesthesiologist will gently assist your breathing by placing a mask over your nose and mouth. 
This may be done for up to 15 minutes. Anesthesiologists are trained and routinely assist patient 
to breathe in the operating room. If this is done, you may notice a circular region of redness around 
your mouth and nose. There is also a slight chance that you may experience stomach insufflation 
and vomiting.
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 7 of 14
Subject Identification
Ketamine may cause you to have one or more of the side effects listed below. 

high blood pressure

increased heart rate

irregular hear rate

increased saliva

increased mucus

eye twitching

hallucinations/clear dreams that may seem real

confusion

irritated feeling when waking up

floating sensation (feeling “out-of-body”) lasting from minutes to hours.

breathing problems, coughing

nausea, vomiting

twitching, muscle jerks, and muscle tension

increased thirst

headaches

metallic taste

constipation

blurry or double vision

involuntary eye movements

low mood or suicidal thoughts

allergic reaction (skin rash)

pain at site of injection

increased intraocular pressure

ulcerations and inflammation in the bladder
When giving any general anesthetic, there is always the possibility of very rare side effects or 
complications such as nerve damage, heart attack, brain damage, or even death. However, giving 
ketamine for sedation and maintenance of general anesthesia, at the doses you will receive in this 
study, is a standard practice in nearly every surgical center nationwide. Therefore, while the side 
effects and complications listed above are possible, life threatening side-effects are highly 
unlikely.
Any acute changes in heart rate or blood pressure observed during the study will be treated using 
standard anesthesiology practices. 
Risks of Taking Glycopyrrolate
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 8 of 14
Subject Identification
Glycopyrrolate is a drug that is used in the operating room every day.  It is used to treat heart rate 
changes while a person is under general anesthesia. Glycopyrrolate may be given to you through 
the intravenous catheter to treat excessive salivation.
Common problems with glycopyrrolate (more than 1 out of 10) include dry mouth. Less common 
(between 1 and 10 out of 100) are abnormal heart rhythm (your heart not beating at an even pace),  
nausea, blurry vision and difficulty urinating.
Risks of Labetalol
Labetalol is a drug that is used to treat blood pressure changes while a person is under general 
anesthesia. Labetalol may be given to you through the intravenous catheter to decrease your blood 
pressure to a normal range. An anesthesiologist will monitor your blood pressure and heart rate 
and will give you labetalol to treat high blood pressure, if needed. Risks of labetalol include low 
blood pressure and low heart rate. 
Risks of Intravenous (IV) Catheter 
You may have a bruise (a black and blue mark) or pain where we place the IV. There is also a 
small risk of infection, lightheadedness, and fainting. 
Risk of EEG Electrodes
There is a possibility that you may experience some redness or itching where the electrodes are 
placed. 
Risks of Pain Stimuli Cuff 
You may have a bruise (a black and blue mark) on your leg from the inflation of the cuff. In our 
experience, this is infrequent (occurs in less than 5 out of 100 people). A simple button press 
(controlled by the study team) can rapidly deflate the cuff, to make sure you are safe. The pain 
cuff will only be used when you are awake enough to talk to study team members. You can 
request that the cuff be deflated if it is too painful.
Risks of Allergic Reaction
As with any drug, an allergic reaction can occur.  Allergic reactions can be mild or more serious, 
and can even result in death.  Common symptoms of an allergic reaction are rash, itching, skin 
problems, swelling of the face and throat, or trouble breathing. If you think you are having an 
allergic reaction, tell the study doctor right away.  
Risks to an Embryo or Fetus, or to a Breastfeeding Infant
The effect of ketamine on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding infant, is unknown and may be harmful.  Because of these unknown risks, women 
cannot take part in this study if they are:

Pregnant

Trying to become pregnant 
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 9 of 14
Subject Identification

Breastfeeding
If you are a menopausal woman and have not had a period for the past 12 months or more, you 
will not need to have a pregnancy test.  Also, if you have had any well-documented method of 
surgical sterilization, you will not need to have a pregnancy test.  The documented methods of 
surgical sterilization include having had a hysterectomy (removal of the uterus with or without the 
ovaries), bilateral oophorectomy (removal of both ovaries), a tubal ligation (having your tubes 
tied), or transvaginal occlusion (plugging the opening of the tubes with a coil.
What are the possible benefits from being in this research study?
You will not benefit from taking part in this study.  What we learn in this study may help 
researchers develop improved anesthetics and anesthesia monitoring equipment in the future.  It 
may also help researchers develop better pain management strategies. This may improve medical 
care for patients receiving anesthesia in the future.
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part?
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive.
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study.
What should I do if I want to stop taking part in the study?
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed.
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed.
Will I be paid to take part in this research study?
We will pay you $500 if you complete both study visits. 
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 10 of 14
Subject Identification
If you complete the screening visit in good faith and are unable to continue for medical reasons, 
you will be compensated $50. 
We will give you parking vouchers (coupons) to pay for your parking in the MGH garage during 
study visits. 
What will I have to pay for if I take part in this research study?
Study funds will pay for certain study-related items and services.  We may bill your health 
insurer for, among other things, routine items and services you would have received even if you 
did not take part in the research.  You will be responsible for payment of any deductibles and co-
payments required by your insurer for this routine care or other billed care.  If you have any 
questions about costs to you that may result from taking part in the research, please speak with 
the study doctors and study staff.  If necessary, we will arrange for you to speak with someone in 
Patient Financial Services about these costs.”
What happens if I am injured as a result of taking part in this research 
study?
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer.
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form.
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form.
If I have questions or concerns about this research study, whom can I 
call?
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 11 of 14
Subject Identification
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.
Oluwaseun Johnson-Akeju, MD, MMSC, is the person in charge of this research study.  You can 
call him at 617-724-7200 Monday-Friday, 8am to 5pm.  He can also be reached 24 hours a day, 
7 days a week at (617) 726-2000, pager #13024.
If you have questions about the scheduling of appointments or study visits, call Jacob Gitlin at 
617-643-2896 Monday-Friday, 8am to 5pm or by email at jgitlin1@partners.org.
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900.
You can talk to them about:

Your rights as a research subject

Your concerns about the research

A complaint about the research
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help.
If I take part in this research study, how will you protect my privacy?
Federal law requires Partners to protect the privacy of health information and related information 
that identifies you.  We refer to this information as “identifiable information.”
In this study, we may collect identifiable information about you from:

Past, present, and future medical records

Research procedures, including research office visits, tests, interviews, and 
questionnaires
Who may see, use, and share your identifiable information and why:

Partners researchers and staff involved in this study

The sponsor(s) of the study, and people or groups it hires to help perform this research  or 
to audit the research

Other researchers and medical centers that are part of this study
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 12 of 14
Subject Identification

The Partners ethics board or an ethics board outside Partners that oversees the research

A group that oversees the data (study information) and safety of this study

Non-research staff within Partners who need identifiable information to do their jobs, 
such as for treatment, payment (billing), or hospital operations (such as assessing the 
quality of care or research)

People or groups that we hire to do certain work for us, such as data storage companies, 
accreditors, insurers, and lawyers

Federal agencies (such as the U.S. Department of Health and Human Services (DHHS) 
and agencies within DHHS like the Food and Drug Administration, the National 
Institutes of Health, and the Office for Human Research Protections) state agencies, and 
foreign government bodies that oversee, evaluate, and audit research, which may include 
inspection of your records

Public health and safety authorities,  if we learn information that could mean harm to you 
or others (such as to make required reports about communicable diseases or about child 
or elder abuse)

Other researchers within or outside Partners, for use in other research as allowed by law.
Certificate of Confidentiality
A federal Certificate of Confidentiality (Certificate) has been issued for this research to add 
special protection for information and specimens that may identify you.  With a Certificate, 
unless you give permission (such as in this form) and except as described above, the researchers 
are not allowed to share your identifiable information or identifiable specimens, including for a 
court order or subpoena. 
Certain information from the research will be put into your medical record and will not be 
covered by the Certificate.  This includes records of medical tests or procedures done at the 
hospitals and clinics, and information that treating health care providers may need to care for 
you.  Please ask your study doctor if you have any questions about what information will be 
included in your medical record.  Other researchers receiving your identifiable information or 
specimens are expected to comply with the privacy protections of the Certificate.  The Certificate 
does not stop you from voluntarily releasing information about yourself or your participation in 
this study.
Even with these measures to protect your privacy, once your identifiable information is shared 
outside Partners, we cannot control all the ways that others use or share it and cannot promise 
that it will remain completely private. 
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 13 of 14
Subject Identification
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your identifiable information.  Your permission to use and share 
your information does not expire.  
The results of this research may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifiable information will not be used for these 
purposes without your specific permission.
Your Privacy Rights
You have the right not to sign this form that allows us to use and share your identifiable 
information for research; however, if you don’t sign it, you can’t take part in this research study.
You have the right to withdraw your permission for us to use or share your identifiable 
information for this research study.  If you want to withdraw your permission, you must notify 
the person in charge of this research study in writing.  Once permission is withdrawn, you cannot 
continue to take part in the study.
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
purposes, such as to comply with law or maintain the reliability of the study.  
You have the right to see and get a copy of your identifiable information that is used or shared 
for treatment or for payment.  To ask for this information, please contact the person in charge of 
this research study.  You may only get such information after the research is finished.
Informed Consent and Authorization
Statement of Person Giving Informed Consent and Authorization

I have read this consent form.

This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study.

I have had the opportunity to ask questions.

I understand the information given to me.
Signature of Subject:
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2018
Page 14 of 14
Subject Identification
I give my consent to take part in this research study and agree to allow my identifiable 
information to be used and shared as described above.
Subject
Date
Time (optional)
Signature of Study Doctor or Person Obtaining Consent:
Statement of Study Doctor or Person Obtaining Consent

I have explained the research to the study subject.

I have answered all questions about this research study to the best of my ability.
Study Doctor or Person Obtaining Consent
Date
Time (optional)
Consent Form Version Date:  10/17/2018
Consent Form Title: Ket_Consent_Form(COC)_AME5_Clean
IRB Protocol No: 2018P000417
Consent Form Valid Date: 10/24/2018 12:00:00 AM
IRB Expiration Date: 5/18/2019 12:00:00 AM
Sponsor Protocol No: "N/A"
Sponsor AME No: "N/A"
IRB AME No: AME5