Characterizing the Electroencephalogram Signature of Fentanyl During Induction of General Anesthesia
Conditions: Anesthesia
Sponsor: Massachusetts General Hospital

Characterizing the Electroencephalogram 
Signature of Fentanyl During Induction of 
General Anesthesia 
 
NCT number: NCT03866278 
 
Version Date:  12/5/2019 
 
 

Characterizing the Electroencephalogram Signature of 
Fentanyl During Induction of General Anesthesia 
PRINCIPAL INVESTIGATORS: Patrick L. Purdon, Ph.D. 
 
CO-INVESTIGATORS: Emery Brown, M.D., Ph.D., Eric T. Pierce, M.D., Ph.D., Andrew C. Mullen, 
S.Bc. 
VERSION DATE:  12/5/2019 
BACKGROUND AND SIGNIFICANCE  
Each day in the United States, more than 50,000 patients receive general anesthesia for 
surgical procedures (Barash, 2013). The state of general anesthesia has four characteristics: 
hypnosis, amnesia, analgesia, and lack of movement (Barash, 2013). While historically 
anesthesiologists rely on pharmacokinetics to track the loss of consciousness, new research in 
anesthesiology has identified the salient features of the electroencephalogram (EEG) that 
correlate to states of sedation and unconsciousness induced by different anesthetic drugs (Purdon 
et al., 2015). While the EEG features of many sedative-hypnotic anesthetics have been well-
characterized, the opioid analgesic drugs have not been analyzed in detail in this way. A 
characterization of the EEG signatures of opioid analgesic drugs could be useful in monitoring 
and titrating the effects of these drugs.  
Fentanyl is one of the most commonly used opioid analgesic drugs.  Prior to induction of 
general anesthesia, fentanyl is frequently administered to blunt the nociceptive response to 
intubation.  A typical scenario is to administer 2 to 4 mcg/kg of fentanyl first, followed by a 
sedative hypnotic drug such as propofol to induce general anesthesia. In this study, we propose 
to administer a total of either 4 or 6 mcg/kg, followed by a sedative hypnotic drug. The higher 
total dose of fentanyl, 6 mcg/kg, will be administered if the patient is still responsive to 
somatosensory stimulation after receiving 4 mcg/kg of fentanyl. We will be using a patient’s 
ideal body weight (IBW) scalar (Devine 1974) to calculate the appropriate dosage of drug. At 
this dose, fentanyl will serve to blunt nociception during intubation, but will also contribute to 
intraoperative pain management.  During this time, we will record the EEG using standard EEG-
based anesthetic monitors that are routinely used in the operating room.  We will assess the 
patient’s level of responsiveness using an auditory task and ulnar nerve stimulation.  These 
measurements will allow us to identify the EEG signatures of fentanyl for future use in EEG-
based anesthetic monitoring. 
 
 
SPECIFIC AIMS 
 
The specific aims of this study are: 
 
Specific Aim 1: Identify and analyze electroencephalogram (EEG) signals correlated with 
administration of fentanyl. 
 
 
Specific Aim 2: Characterize the relationship between fentanyl-induced EEG signals and 
autonomic signals such as respiration, heart rate, and blood pressure. 
 

Specific Aim 3: Compare the fentanyl-induced EEG signals with those observed after induction 
of general anesthesia. 
 
STUDY PROCEDURES 
 
Overview 
 
 
During this study we will measure EEG and responses to auditory and ulnar nerve stimuli 
during induction of general anesthesia in surgical patients.  The anesthetic will be administered 
according to a typical sequence in which fentanyl is first administered, followed by a sedative 
hypnotic drug for induction of general anesthesia.  The primary difference is that, in this study, we 
will record the EEG and response data for a short period of time after initial administration of 
fentanyl and prior to administration of a sedative hypnotic drug to induce general anesthesia 
(Figure 1).  The choice of anesthetics and anesthetic doses will be at the discretion of the 
anesthesiologist caring for the patient. 
 
The protocol has been reviewed and approved by the Clinical Operations Committee in the 
MGH Department of Anesthesia, Critical Care and Pain Management, who confirm that the 
anesthetic protocol is consistent with routine clinical care (see attached letter from the Clinical 
Operations Committee). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
EEG recordings 
 
EEG data will be recorded from the EEG-based anesthesia monitors that are currently being 
used in all operating rooms at Massachusetts General Hospital (Sedline, Masimo Corporation, 
Irvine, CA).  
 
 
Anesthetic Procedures 
 
The anesthetic will be administered according to a typical sequence in which fentanyl is 
first administered, followed by a sedative hypnotic drug for induction of general anesthesia. The 
fentanyl will be administered in two boluses of 2 mcg/kg, spaced 2 minutes apart, for a total 
amount of 4 mcg/kg of fentanyl.  Weight will be calculated using the ideal body weight (IBW) 
scalar. 
If the subject is conscious after receiving 4 mcg/kg fentanyl, they will receive an 
additional 2 mcg/kg bolus of fentanyl after 2 minutes of observation. Consciousness will be 
determined by the subject’s continued participation in the behavioral test, as described below. If 
the subject has stopped responding to the auditory stimuli, a study team member will attempt to 
rouse the subject, in the following order: (1) verbally, (2) physically by tapping the subject on the 
Figure 1 Proposed recording period and anesthetic sequence versus typical clinical practice during which fentanyl will be the 
sole anesthetic agent used. The third bolus is only administered in the event that the patient is responding to somatosensory 
stimulation two minutes after the second bolus of fentanyl. 
. 

shoulder, and finally, (3) physically with electrical stimulation through the ulnar nerve 
electrodes. If the subject responds to any of these stimuli, they will be given the third 2 mcg/kg 
bolus of fentanyl and monitored for 5 minutes. If the subject does not respond to these stimuli, 
the subject will not be given any additional fentanyl. 
We will then record 5 minutes of EEG and behavioral responses, prior to administration 
of the sedative-hypnotic drug for general anesthesia.  During this time, the patient will be 
ventilated, as needed, by bag mask ventilation. After this 5-minute period, general anesthesia 
will be induced according to the clinical anesthesiologist’s discretion. Again, as stated above, the 
primary difference between this protocol and a typical anesthetic induction is the few minutes 
added between fentanyl administration and induction of general anesthesia.  Ventilation will be 
closely monitored and assisted with anesthesia mask ventilation as needed during the 
experimental period.  If the ventilation becomes difficult, the protocol will be abandoned and 
induction will be initiated as per the anesthesia team’s judgment. 
No pre-medication prior to induction will be given, but if needed, midazolam will be 
administered as clinically indicated. At all times, the patient’s clinical anesthesiologist will have 
full control in managing the anesthetic, and may choose to intervene at any time before, during, 
or after the 5-minute recording period if deemed clinically necessary.  As part of this, prior to the 
start of the study, the patient’s clinical anesthesiologist may decide that the protocol is 
inappropriate for the patient, in which case the clinical anesthesiologist will carry out the 
induction of general anesthesia as they deem most appropriate. 
 
 
Auditory and Somatosensory stimuli 
 
The subject will be asked to listen to a series of sounds played through headphones, and to 
respond via button press to identify the sound as either a train of clicks, or verbal stimuli.  The 
auditory stimulus will begin prior to administration of fentanyl and will continue through the end 
of the induction period.  If a patient has stopped responding to the auditory stimuli within the 5-
minute period between administration of fentanyl and induction of general anesthesia, 250msec 
ulnar nerve stimuli at 60mA will be performed to assess whether the subject can be aroused to 
consciousness. Responses to this ulnar nerve stimuli, including movement, grimacing, eye 
opening, or verbal responses, will be noted. A member of the study team will attempt to rouse the 
subject with verbal stimuli or tapping the subject’s shoulder before using ulnar nerve stimulation. 
 
 
 
Data from the electronic medical record for general anesthesia and sedation 
 
 
We will gather data from the electronic medical record on the drugs given, their dosage, 
and the times when they are administered, as well as physiological parameters such as heart rate, 
respiration rate, and blood pressure. The fidelity of the EtCO2 waveform depends on how well 
the ventilation mask fits and seals against the patient’s face.  Therefore, to provide redundancy, 
we will use a chest belt as an additional measure of respiration. 
 
 
 

Data Analysis 
 
 
Spectral analyses on the EEG will be performed in off-line analysis. The EEG power in 
different frequency bands will be analyzed as a function of auditory task behavior, the predicted 
drug plasma concentrations, and the physiological recordings of respiration rate, end-tidal CO2, 
heart rate, blood pressure, and oxygen saturation. 
 
Sample Size Calculation 
 
 
We are observing frontal EEG to detect changes from baseline spectral features when 
fentanyl is administered and desire detecting an effect size of approximately 10%.  Using 
standard sample size and power calculations based on normally-distributed effects and errors, 
with an equal value standard deviation (SNR=0.1), type 1 error of 0.05, and desired power of 0.8, 
we arrive at a sample size of 80.  
 
SUBJECT RECRUITMENT, SELECTION, AND ENROLLMENT 
 
These studies will take place at Massachusetts General Hospital. Patients scheduled to 
undergo surgery lasting 2 hours or greater, in the age range of 18 to 65, will be eligible for this 
study.  
 
Subject Recruitment and Enrollment 
 
Potential subjects will be identified by anesthesiologists, who are not the patient’s 
anesthesiologist, on our study staff. Potential subjects will be approached in the preoperative 
period by an anesthesiologist or a preoperative nurse to assess their interest in research 
participation. Interested patients will then be approached by anesthesiologist co-investigators on 
our study staff. A research assistant or coordinator may query EPIC for potential subjects and 
will confirm on EPIC that a potential subject identified by the physician investigator meets 
eligibility requirements.  A research assistant or coordinator may query EPIC for potential 
patients and will confirm that potential subjects identified by the physician investigator meet 
eligibility requirements. Patients undergoing surgeries anticipated to take longer than 2 hours, 
and that typically require intravenous opioids for post-operative management, will be selected, 
since in these patients use of fentanyl during the induction period would be appropriate 
clinically. Permission for patient participation will be obtained from the patient’s surgeon prior 
to enrollment. Subjects will be approached during the pre-operative period to describe the study 
and obtain consent. Every effort will be made to avoid protocol related delays in starting surgery. 
Consent will be obtained by a study clinician in the pre-anesthesia or perioperative ward 
prior to anesthesia and surgery.   Prior to the study, each subject will sign witnessed, informed 
consent for this study. There will be no randomization or treatment assignment as there is no 
therapy being studied.  
 
Subject Selection 
Only those patients capable of giving their own consent will be considered for this study.  
All study subjects will be American Society of Anesthesiologists (ASA) physical status 
classification P1 to P3. That is, all study subjects will have at most mild to moderate systemic 

disease. A subject's medical history will be reviewed to rule out active and chronic medical 
problems. 
 
Conditions that will exclude subjects from the study entirely: 
 
Craniofacial abnormalities 
 
 
 
Allergies to fentanyl, bisulfite, eggs or egg products, latex, soybeans, soybean oil 
 
BMI ≤  35 (kg/m2) 
 
Known or suspected difficult intubation 
 
Known or suspected need for rapid sequence induction and intubation 
 
History of obstructive sleep apnea requiring CPAP 
 
History of uncontrolled gastroesophageal reflux disease (GERD) 
 
Opiate use within 24 hours 
 
History of opiate abuse within 3 years 
 
RISKS AND POTENTIAL BENEFITS 
Risk and Discomfort 
There is risk of bradycardia, hypotension requiring pressors, as well as transient muscle 
rigidity and difficulty ventilating; however, these are not added risks as they are existing side-
effects of general anesthesia. Through rare, it is possible for patients to develop muscle rigidity 
after administration of fentanyl.  When such cases occur during routine clinical care, 
anesthesiologists administer a fast-acting muscle relaxant such as succinylcholine to counteract 
this side effect.  The standard anesthesia drug tray is stocked with succinylcholine syringes for 
this and other reasons.  In our study, in the rare event of muscle rigidity, the anesthesiologist will 
administer succinylcholine as they would do in routine clinical care.  If muscle rigidity occurs, 
no additional fentanyl will be administered.  Subjects may experience slight transient discomfort 
from the stick-on Masimo EEG sensor as well as from the respiration band.  If the patient can be 
roused to consciousness during the 250-millisecond ulnar nerve stimulation, they may experience 
transient discomfort.  In this case, the patient will have already received boluses of fentanyl 
reducing this discomfort 
Potential Benefits 
There are no direct benefits for subjects.  However, the knowledge gained from this study 
may help to improve anesthesia monitoring, which may benefit future patients. 
 
MONITORING AND QUALITY ASSURANCE 

Monitoring the validity and integrity of the data and adherence to the IRB-approved 
protocol will be the primary responsibility of the Principal Investigator, Patrick L. Purdon, Ph.D. 
For each case, they will confirm that all informed consent has been properly obtained, and that 
all data is appropriately recorded and maintained.  This study involves no more than minimal 
risk, thus no formal DSMB is planned. In accordance with the PHRC guidelines, adverse events 
and unanticipated problems involving risks to subjects or others will be reviewed by the clinical 
co-investigator, Dr. Eric Pierce, who will judge whether event(s) were expected or not, or related 
or not to the study.  Individual reports of adverse events will be submitted to the PHRC/IRB 
promptly. Adverse events and unanticipated problems involving risks to subjects or others will 
be reported to the PHRC in accordance with PHRC adverse event and unanticipated problems 
reporting guidelines.  In addition, the investigator will also determine the best course of action to 
ensure subject safety.   
 
Privacy of data will be ensured by de-identifying data. Data will be stored on password-
protected and encrypted MGH Partners computers.  Each subject will be assigned an 
alphanumeric code (with the key kept in a password protected file accessible only to study staff).  
Any data that may require physical transfer from one place to another will be performed using 
removable data storage devices encrypted under the 256-bit Advanced Encryption Standard 
(AES), as per Partners recommendations.  
 
 
REFERENCES 
 
Barash, Paul G. Handbook of Clinical Anesthesia. Lippincott Williams & Wilkins/Wolters  
Kluwer, 2013 
 
Devine, B. J. Gentamicin therapy. Drug Intell Clin Pharm, 1974;8:650-5 
 
Purdon, Patrick L., et al. “Clinical Electroencephalography for Anesthesiologists.”  
Anesthesiology, vol. 123, no. 4, 2015, pp. 937–960., doi:10.1097/aln.0000000000000841.