EEG to Monitor Propofol Anesthetic Depth in Infants and Toddlers
Phase: NA
Conditions: Electroencephalography Spectral Edge Frequency, Anesthetic Depth
Sponsor: Children's Hospital of Philadelphia

 
Template version: January 30, 2020 
 
 
 
Title: 
EEG to monitor propofol anesthetic depth in infants and 
toddlers 
Short Title 
EEG propofol depth young children 
 
Study Drug  
Propofol 
 
Sponsor: 
 
The Children’s Hospital of Philadelphia 
eIRB Number 
 
22-019941 
Protocol Date: 
 
October 10, 2022 
Amendment 1 Date: November 8, 2022 
 
Amendment 3 Date: June 13, 2023 
Amendment 2 Date: January 17, 2023 
Amendment 4 Date: September 8, 2023 
 
Amendment 5 Date: December 11, 2023 
 
 
 
 
 
 
 
 
 
 
Study Principal Investigator 
Ian Yuan, MD 
Department of Anesthesiology and Critical Care Medicine 
The Children’s Hospital of Philadelphia 
34th St and Civic Center Blvd, 9th floor 
 Philadelphia, PA 19104 
Phone: 215-590-1866 (Office)  
Email: yuani@chop.edu 

  
 
 
 
 
ii 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms............................................................................. iv 
Abstract .................................................................................................................................. v 
Protocol Synopsis ................................................................................................................. vii 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
RELEVANT LITERATURE AND DATA ..................................................................................................... 2 
1.3 
COMPLIANCE STATEMENT .................................................................................................................... 4 
2 
STUDY OBJECTIVES .............................................................................................................................. 5 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................ 5 
2.2 
SECONDARY OBJECTIVES ..................................................................................................................... 5 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 5 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 5 
 
Screening Phase .............................................................................................................................. 5 
 
Study Interventional Phase .............................................................................................................. 5 
EEG Monitoring ........................................................................................................................................... 6 
 
Laboratory Tests ............................................................................. Error! Bookmark not defined. 
3.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................... 6 
 
Duration of Patient Study Participation.......................................................................................... 6 
 
Total Number of Study Sites/Total Number of Patients Projected .................................................. 6 
3.3 
STUDY POPULATION ............................................................................................................................. 6 
 
Inclusion Criteria ............................................................................................................................ 6 
 
Exclusion Criteria ........................................................................................................................... 7 
4 
STUDY PROCEDURES ............................................................................................................................ 7 
4.1 
SCREENING PHASE ............................................................................................................................... 7 
4.2 
STUDY INTERVENTIONAL PHASE .......................................................................................................... 7 
 
EEG Recording ............................................................................................................................... 7 
 
Stimuli ............................................................................................................................................. 7 
4.3 
PATIENT COMPLETION/WITHDRAWAL ................................................................................................. 8 
5 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 9 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS .................................................. 9 
 
Medical Record Review ................................................................................................................... 9 
 
EEG Monitoring .............................................................................................................................. 9 
 
Propofol Dosing .............................................................................................................................. 9 
 
Stimuli ............................................................................................................................................. 9 
 
Responses to Stimuli ...................................................................................................................... 11 
 
Blood collection ............................................................................................................................ 11 
 
Dixon Up-Down Technique ........................................................................................................... 11 
 
Achieving SEF target .................................................................................................................... 11 
5.2 
LABORATORY TEST ............................................................................................................................ 12 
5.3 
SAFETY EVALUATION ......................................................................................................................... 12 
5.4 
NON-EVALUABLE SUBJECTS ............................................................................................................... 12 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 12 
6.1 
PRIMARY ENDPOINT ........................................................................................................................... 12 
6.2 
SECONDARY ENDPOINTS .................................................................................................................... 12 

 
 
 
 
 
iii 
 
iii 
6.3 
STATISTICAL METHODS...................................................................................................................... 12 
 
Baseline Data ................................................................................................................................ 12 
 
EEG SEF ....................................................................................................................................... 13 
 
Propofol Ce ................................................................................................................................... 13 
 .................................................................................................................................................................... 14 
 
Sample Size and Power ................................................................................................................. 14 
6.4 
Safety Analysis .............................................................................................................................. 14 
7 
SAFETY MANAGEMENT ..................................................................................................................... 15 
7.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 15 
7.2 
ADVERSE EVENT REPORTING ............................................................................................................. 15 
7.3 
DEFINITION OF AN ADVERSE EVENT .................................................................................................. 15 
7.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ........................................................................... 15 
 
Relationship of SAE to study intervention ..................................................................................... 16 
7.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ...................................... 16 
 
Follow-up report ........................................................................................................................... 16 
8 
STUDY ADMINISTRATION ................................................................................................................. 16 
8.1 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 16 
8.2 
CONFIDENTIALITY .............................................................................................................................. 17 
8.3 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 17 
 
Data and Safety Monitoring Plan ................................................................................................. 17 
 
Risk Assessment ............................................................................................................................. 17 
 
Potential Benefits of Trial Participation ....................................................................................... 18 
 
Risk-Benefit Assessment ................................................................................................................ 18 
8.4 
RECRUITMENT STRATEGY .................................................................................................................. 19 
8.5 
INFORMED CONSENT AND HIPAA AUTHORIZATION .......................................................................... 19 
3.1.3 
Individuals with Limited English Proficiency ............................................................................... 19 
8.6 
PAYMENT TO PATIENTS/FAMILIES ...................................................................................................... 19 
9 
PUBLICATION ........................................................................................................................................ 19 
10 
REFERENCES ......................................................................................................................................... 20 
 

  
 
 
 
 
iv 
 
iv
ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse events 
EEG 
Electroencephalography 
Ce 
Effect site concentration 
SEF 
Spectral Edge Frequency 
IV 
Intravenous 
Laryngoscopy 
Using a laryngoscope to visualize the vocal cords. 
Intubation 
Placement of an endotracheal tube after laryngoscopy 
Infant  
28 days to 12 months of age  
Toddler 
12 -24 months of age 
Child  
2 yrs to 12 yrs of age 
LMA 
Laryngeal Mask Airway 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
v 
 
v
ABSTRACT 
Context: (Background) 
Sevoflurane inhalation and propofol intravenous anesthesia are the mainstays of delivering 
general anesthesia in children. Propofol anesthesia in children is gaining popularity due to 
fewer respiratory complications, less post-operative nausea vomiting and emergence 
delirium, compared to sevoflurane. However, unlike sevoflurane, the pharmacodynamics of 
propofol is less studied in infants and toddlers, particularly the biomarker for propofol brain 
effect site concentration (Ce), indicative of anesthetic depth. The lack of a real-time 
biomarker often results in over- or under-dosing of propofol in clinical practice. The goal of 
this study is to utilize electroencephalography (EEG) as the biomarker of propofol effect site 
concentration and clinical anesthetic depth, thereby improving the safety and efficacy of 
propofol anesthesia in this population. 
 
Objectives: (primary and important secondary objectives)  
Primary: In infants and toddlers receiving propofol anesthesia, EEG will be recorded while 
the patient undergoes three stimuli used to assess anesthetic depth (placement of oral 
pacifier, electrical stimulation, and laryngoscopy). The EEG index (spectral edge frequency-
SEF) where 50% of patients do not respond to each of the three stimuli will be determined 
as the biomarker of propofol clinical anesthetic depth. 
Secondary: In the same cohort, the regression between EEG SEF and plasma propofol levels 
will be determined to assess relationship between EEG SEF and propofol Ce. 
 
Study Design:  
Sequential allocation prospective trial.  
 
Setting/Participants: 
The study will be performed at CHOP. Up to 150 patients who are undergoing procedures 
under general anesthesia will be enrolled to produce 120 evaluable patients with 60 in each 
of two age groups (3-12mo and 13-24mo). 
 
Study Interventions and Measures:  
For each patient, up to three stimuli will be done in sequence (placement of oral pacifier, 
electrical stimulation, and laryngoscopy—a clinically required procedure). Propofol dosing 
will be adjusted to achieve a target EEG SEF for each stimulus. EEG SEF is used as a 
biomarker of anesthetic depth. The response to the stimulus and EEG SEF will be recorded, 
along with obtaining a 1ml blood sample. Obtaining the blood sample may not always 
coincide with the stimulus and up to three blood samples may be drawn per subject. 
Between different stimuli on the same patient, adjustments to propofol dosing may be 

  
 
 
 
 
vi 
 
vi
required to achieve a different SEF target. After each study patient, the response to the 
stimulus will be used to adjust the EEG SEF target for the next patient.  
At the end of the study, the median EEG SEFs (EEG SEF50) for each of the three stimuli 
will be determined. The propofol Ce that corresponds to each EEG SEF will be determined 
from a regression curve of SEF vs propofol plasma concentration obtained from 1ml of 
patient blood and measured in a pharmacodynamics laboratory. The study will only be 
performed by the investigators listed in the study. 
 

 
page vii 
  
vii 
 
PROTOCOL SYNOPSIS 
Study Title 
EEG to assess propofol anesthetic depth in infants and toddlers 
Funder 
Departmental funds 
Study Rationale 
Sevoflurane inhalation and propofol intravenous anesthesia are the 
mainstays of delivering general anesthesia in children. Propofol 
anesthesia in infants and toddlers is gaining interest due to fewer 
respiratory complications, less post-operative nausea vomiting and 
emergence delirium, compared to sevoflurane anesthesia. However, 
the pharmacodynamics of propofol has not been well studied in 
infants and toddlers, and there is no readily available method to 
monitor the depth of propofol anesthesia, which often results in 
over- or under-dosing of propofol. Anesthetic dosing and the 
resultant brain effect-site concentration (Ce) depend on the desired 
clinical endpoint during a procedure. In clinical practice, the three 
main endpoints of anesthesia depth are unconsciousness, no 
response to surgical incision, and no response to laryngoscopy. 
Electroencephalography (EEG) can be used to monitor anesthetic 
depth during propofol anesthesia in children and adults, as EEG 
parameters (spectral edge frequency-SEF) decrease predictably with 
increasing propofol Ce and anesthetic depth. This study will use 
EEG SEF to monitor anesthetic depth in infants and toddlers during 
three stimuli (placement of oral pacifier, electrical stimulation, and 
laryngoscopy—a clinically required procedure), which reflect the 
three endpoints of clinical anesthesia depth. The median EEG SEF 
where 50% of patients do not respond to each of the three stimuli 
will be determined, along with the relationship between EEG SEF 
and propofol effect site concentration (Ce), as measured from 
plasma propofol levels at the time the EEG SEF was recorded. 
Results from this study should improve the safety and efficacy of 
propofol anesthesia in infants and toddlers by confirming EEG SEF 
as a biomarker of  propofol anesthetic depth, thereby improving the 
accuracy of dosing to avoid over- and under-dosing.  
Study Objective(s) 
Primary  
In infants and toddlers receiving propofol anesthesia for a procedure 
determine the three EEG SEFs where 50% of patients do not respond 
to the three stimuli (placement of oral pacifier, electrical stimulation, 
and laryngoscopy—a clinically required procedure). 

 
page viii 
  
viii 
 
Secondary 
In the same cohort, determine the dose-response relationship 
between EEG SEF and propofol Ce, as measured from plasma 
propofol levels. 
Study Design 
 
Sequential allocation trial using Dixon’s up-down technique. To 
achieve the EEG SEF target, initial propofol dosing will be based on  
a published age-based dosing table used clinically at CHOP. The 
EEG SEF target for a specific stimulus will be determined by the 
previous patient’s response to that same stimulus. If the previous 
patient responded to the stimulus, then the current patient will have 
a lower SEF target for the same stimulus. Conversely, if the 
previous patient did not respond to the stimulus, then the current 
patient will have a higher SEF target for the same stimulus. 
In the same patient, propfol dose adjustments may be needed 
between stimuli to achieve different SEF targets. The patient 
response to stimulus and EEG SEF will be recorded, along with a 
1ml blood sample to determine propofol plasma level at a later date 
in the pharmacodynamic laboratory. The study will only be 
performed by the investigators listed in the study. 
Patient Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1) Children 3 to 24 month old undergoing a procedure 
2) Planned laryngoscopy and endotracheal intubation or LMA 
placement for clinical care 
3) Planned propofol anesthesia for anesthesia maintenance. 
4) ASA < III. 
5) Muscle relaxant not indicated per planned clinical care for 
laryngoscopy/intubation. 
6) Anticipated procedure duration approximately < 2h40min 
 
Exclusion Criteria 
1) Patients undergoing an emergency procedure 
2) Known severe neurological disease which might result in 
abnormal EEG SEF. 
3) Deformities of forehead (difficult EEG sensor placement). 
4) Known difficult airway. 
5) Allergy to propofol. 

 
page ix 
  
ix 
 
6) Attending anesthesiologist on record caring for patient plans to 
administer additional IV medication besides propofol during study 
phase. 
7) Currently on anti-seizure medication (might alter propofol 
pharmacodynamics). 
Number Of Patients  
 
Up to 150 enrolled patients to produce 120 evaluable patients. 
Study Duration 
Each patient’s participation will last from start of anesthesia to the 
last study stimulus. 
Study Phases 
Screening 
 
Study 
Laboratory   
From placement of second intravenous (IV) line or bolus of 
propofol (if IV is already present prior to induction) to the end of 
the last stimulus performed. Eligibility screening via reviewing 
procedure schedule and obtaining informed consent.  
 
The propofol plasma concentration will be determined in the 
laboratory (Institutional Core Lab at CHOP) via batch processing of 
collected blood samples. 
Safety Evaluations 
Patient safety will be monitored by adverse events (e.g. 
bronchospasm, laryngospasm) and vital signs (e.g. hypotension). 
Statistical And 
Analytic Plan 
The median EEG SEF (SEF50) where half of the patients do not 
respond to a particular stimulus will be determined for each of the 
three stimuli. For each stimulus, each SEF crossover pair (Yes to No 
response or vice versa) will be treated as a SEF pair and the mean 
and standard deviation of all SEF pairs will determine the median 
SEF50 and standard deviation. The propofol Ce that corresponds to 
each SEF will be determined through the regression curve between 
plasma propofol concentration and SEF recorded at the time of the 
blood draw.  
DATA AND SAFETY 
MONITORING PLAN 
The PI will be responsible for management of data quality and 
ongoing assessment of safety. The PI will promptly notify the IRB 
of all on-site unanticipated, serious Adverse Events that are related 
to the research activity. Other unanticipated problems related to the 
research involving risk to patients or others will also be reported 
promptly. In addition, an independent DSMB committee: Drs. 
Arjunan Ganesh, Raj Subramanyam, and Tori Sutherland, who are 
not involved in the study will monitor and review the study 
progress, patient safety, and the accuracy and security of the 

 
page x 
  
x 
 
emerging data. Written reports will be filed using the eIRB system 
in accordance with the timeline below.  
 

 
  
1 
 
1 
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Sevoflurane inhalation and propofol intravenous are the two primary drugs to deliver 
general anesthesia in the pediatric population. The pharmacodynamics of sevoflurane on the 
brain, respiratory, and cardiovascular functions have been extensively studied and are well 
known.1 The pharmacodynamics of propofol has not been well studied in the pediatric 
population, particularly in infants and toddlers. Consequently, propofol anesthesia in infants 
and toddlers is dosed without pharmacodynamic knowledge, often resulting in over- or under-
dosing.2-4 This gap in dosing knowledge is ever more relevant, with increased interest in using 
propofol in pediatric anesthesia due to fewer respiratory complications, less post-operative 
nausea vomiting and emergence delirium, compared to sevoflurane.5-7 
Sevoflurane and propofol dosing and the resultant brain effect-site concentration (Ce) 
depend on the desired clinical endpoint during the conduct of anesthesia andthe procedure. 
The three main endpoints of surgical anesthesia are unconsciousness, no response to surgical 
incision, and no response to laryngoscopy. The dose to achieve the desired anesthetic depth 
for each of these three endpoints is different; the dose to unconsciousness is less than the dose 
for lack of response to surgical incision or laryngoscopy. Sevoflurane expired gas 
concentration reflects brain Ce and can be used to guide sevoflurane dosing. The sevoflurane 
dose and corresponding Ce to achieve unconsciousness and block response to a procedure and 
laryngoscopy are known in the pediatric population and differ between infants (3-12 mo), 
toddler (13-23 mo), and children (2-12 years).8,9 Although the propofol dose and 
corresponding Ce for the same three endpoints have been established in adults and older 
children via laboratory measurements of propofol plasma concentration,10,11 they remain 
unknown in infants and toddlers. 
Propofol dosing can be guided by electroencephalography (EEG), which monitors 
brain electrical acitivity and reflects anesthetic depth. EEG parameters have been shown to 
change predictably with increasing propofol Ce in children and adults, and can be used to 
guide propofol dosing to the individual patient.12,13 In adult anesthesia and in pediatric practice 
at CHOP, intraoperative EEG monitoring is used to guide propofol dosing and assess 
anesthetic depth.14,3 Despite the advantages of using EEG to guide propofol dosing in infants 
and toddlers, commonly used EEG proprietary indices (e.g., BIS, PSI) were developed in 
adults and not validated in young children. Non-proprietary EEG parameters, such as the 
spectral edge frequency (SEF) are valid in young children under sevoflurane, but the 
relationship between EEG SEF and propofol Ce have not been established in this young 
population. Furthermore, the relationship between EEG SEF and the three clinical endpoints 
(unconsciousness, lack of response to surgical incision, and lack of response to laryngoscopy) 
is also unknown in this age group. 

 
  
2 
 
2 
The proposed study will determine the pharmacodynamics of propofol on brain, 
respiratory, and cardiovascular function at the three clinical endpoints in infants and toddlers 
receiving propofol anesthesia for a procedure. Brain, respiratory and cardiovascular function 
will be assessed by EEG parameters and vital signs. The propofol Ce at each of the three 
clinical endpoints will be assessed by measuring plasma propofol concentration, which is 
equal to brain concentration at steady state. Although propofol may be combined with other 
agents (opioids, regional anesthesia, dexmedetomidine) during anesthetic maintenance, many 
cases utilize propofol as the sole agent throughout the entire anesthetic (e.g., GI endoscopy, 
bronchoscopy, radiological procedures). The study only involves the induction period 
(induction to intubation), when propofol is commonly given as the sole agent, without 
combination of regional anesthetics, opioids, or other agents. Studies have shown that 
anesthetic overdose is common during the induction period (9.3%),15 underlining the 
importance of determining the appropriate dosing during this period. The results of the study 
should improve the safety and quality of propofol anesthesia for infants and toddlers, and 
provide direct benefit to the study patient by detecting and preventing propofol overdose 
during the induction period. 
 
1.2 Relevant Literature and Data 
Propofol Anesthesia 
Propofol is FDA-approved for “Induction of General Anesthesia Patients ≥ 3 years of age 
and Maintenance of General Anesthesia Patients ≥ 2 months of age”.16 Propofol use in the 
study does not involve a route of administration, dose, patient population, or other factor that 
significantly increases the risk (or decreases the acceptability of the risk) associated with the 
use. 
Propofol anesthesia consist of propofol bolus and infusion, which can be combined 
with regional anesthetic, opioids, dexmedetomidine, and/or muscle relaxant. For this study, 
only propofol will be administered during the study period which lasts from placement of 
the second IV or first propofol dosing until the end of the last stimulus In patients with 
sevoflurane induction, sevoflurane will be washed out (patient expires the gas through 
breathing) prior to assessing EEG SEF and starting the first stimulation. Sevoflurane 
washout typically takes 5 minutes. After the study period (end of last stimulus), the 
anesthetic team on record caring for the patient can administer other medications as planned 
for the procedure. 
 
EEG Monitor 
The Masimo SedLine is a non-invasive 4-channel EEG monitor that is 
portable, easy and fast to apply to the forehead, and displays processed EEG. It is 
FDA-approved for use with adults and is widely used in both the adult and pediatric 
surgical population. We are interested in using the Spectral Edge Frequency (SEF)—a 
non-proprietary EEG parameter, to assess anesthetic depth. The Masimo Sedline’s 

 
  
3 
 
3 
usability and safety profile has been established through our studies (17-014608 and 
19-016071). The safety and efficacy of EEG SEF is not being evaluated as part of this 
study. 
 
EEG Parameters vs Anesthetic Dose 
EEG waveforms can be described using amplitude (how much the EEG wave goes 
up and down) and frequency (how fast the wave goes up and down). Typically, with 
increased anesthetic dose, EEG amplitude increases and frequency decreases. Consequently, 
EEG spectral edge frequency (SEF), the frequency where the majority (95%) of EEG power 
lies, decreases reliably with increased anesthetic dose down to age 3 months.17,18 During 
anesthesia and the procedure SEF is calculated and displayed on Masimo EEG monitor 
every second. In older children very deep propofol anesthesia (high dose), deep propofol 
anesthesia (moderate dose), light propofol anesthesia (low dose), and emergence (residual 
drug not yet cleared) correspond to SEF of <5hz, 8-11hz, 16-18hz, and >20hz, 
respectively.12 In younger children (3-24mo), lighter and deeper anesthesia correspond to 
SEF 11.4-14.3hz and 8.1hz, respectively.18 
 
EEG SEF vs Responses to Stimuli 
During anesthesia and the procedure, anesthetic depth is assessed by the response to 
key stimuli. The key stimuli to assess a response in adults and children include: 1) name 
calling/shake-and-shout (assess consciousness); 2) electrical stimulation (a non-injurious 
substitute for surgical incision), and 3) laryngoscopy (assess readiness for intubation).9,19,20 
Since responses to name calling/shake-and-shout are not applicable to infants and unreliable 
in toddlers, the response to placement of oral pacifier is used to assess consciousness 
instead. Therefore, the three stimuli used in this study are: 1) placement of oral pacifier, 2) 
electrical stimulation, and 3) laryngoscopy—a clinically required procedure. Placement of 
oral pacifier involves placing a soft pacifier inside the patient’s mouth. Electrical stimulation 
is used to assess neuromuscular function but in our study will also be used as a non-injurious 
substitute for surgical incision. Laryngoscopy is clinically required to place the breathing 
tube, regardless of the study. Since placement of the oral pacifier and electrical stimulation 
are stimuli that are not part of standard clinical care, only the investigators on the study will 
be performing the stimulations.  
A positive response to each of the three stimuli is the occurrence of any of the 
following: swallowing, sucking, eye opening, facial movement, gross limb movement 
towards the source of stimulus and additionally for laryngoscopy: breath-holding, closure of 
the vocal cords, and coughing.19-21 These responses typically occur at the subconscious level 
without causing awareness of the stimulus. If a positive response is observed, the stimulus is 
stopped. It is likely that a different anesthetic depth and SEF target is needed for each of the 
three stimuli, which can be achieved by adjusting propofol dosing. From clinical experience, 
in infants and toddlers, consicousness, response to surgical incision, and response to 

 
  
4 
 
4 
laryngoscopy correspond to SEF of approximately >15, 10-15, < 10hz, respectively.17 This 
study will determine the precise SEF for each of the 3 clinical endpoints and thereby 
improve propofol dosing accuracy. The standard method in anesthesia to determine dose 
response to clinical endpoints in patients, such as ones in our study, is the Dixon up-down 
technique.  
 
Dixon Up-Down Technique 
This technique was originally used to determine the anesthetic concentration where 
half of the patients did not move on surgical incision. Over the past 50 years, it has been 
used in anesthesia research to determine the median effective dose (ED50) for other 
anesthetics and stimuli, including the three indicators of anesthetic depth proposed in this 
study.22-24 This sequential allocation trial method can determine pharmacodynamics using a 
smaller number of patients than other methods.24  
 
EEG vs Propofol Ce 
At steady state propofol plasma concentration and brain Ce are equal. This can be 
achieved in approximately 4-6 minutes after a dose change (2-3 times blood to brain half-
time kinetic constant of 2 minutes) and confirmed with stable EEG SEF.16,25 If sevoflurane 
was used during anesthesia induction then sevoflurane will be washed out of the patient 
prior to performing the first stimuli, to avoid residual sevoflurane’s effects on the brain and 
EEG. Sevoflurane washout is accomplished by turning off sevoflurane and allowing the 
patient to breath out the gas, which is how sevoflurane anesthesia is discontinued in clinical 
care at the end of the procedure. Sevoflurane concentration measured from the expired gas 
of the patient is standard of care. Sevoflurane washout is complete when expired sevoflurane 
concentration < 0.2%. Propofol infusion and EEG monitoring will start prior to completing 
sevoflurane washout in order to maintain the anesthetic state while switching from 
sevoflurane to propofol. 
Several studies used propofol plasma concentration to validate the accuracy of 
population pharmacokinetic models in estimating propofol Ce, including two studies in 
older children.4,26-29 The first study found an inverse linear relationship between EEG BIS 
index (a proprietary EEG index) and propofol plasma concentration in children > 6 years 
old.28 The second study found that propofol plasma concentration 3.9 mcg/ml corresponded 
to EEG BIS index of 50 in children 4-11 years old.26 There are few studies looking at the 
association of EEG parameters and propofol plasma concentration in infants and young 
toddlers.  
 
1.3 Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312, 314 and 812 and the Good 

 
  
5 
 
5 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonisation (ICH). Note: Only include the sections of Title 21 if the study is regulated by 
the FDA. Only include ICH compliance if the study will actually comply with these 
requirements. All episodes of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, obtain consent, 
and report unanticipated problems involving risks to patients or others in accordance with 
The Children’s Hospital of Philadelphia IRB Policies and Procedures and all federal 
requirements. Collection, recording, and reporting of data will be accurate and will ensure 
the privacy, health, and welfare of research patients during and after the study.  
 
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
In patients receiving propofol anesthesia fora procedure, determine the three EEG SEFs values 
where 50% of patients do not respond to each of the three stimuli: placement of oral pacifier, 
electrical stimulation, and laryngoscopy—a clinically required procedure. 
 
2.2 Secondary Objectives 
In the same cohort, determine the propofol effect site concentration (Ce), at each EEG SEF 
for placement of oral pacifier, electrical stimulation, and laryngoscopy, as calculated from the 
regression between plasma propofol levels and EEG SEF recorded at the time of the blood 
draw.   
 
 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This is a prospective interventional study to determine EEG SEF and propofol Ce during 
stimuli.   
 
 Screening Phase 
Potential patients will be identified from the procedure schedule using the study inclusion 
and exclusion criteria. Informed consent will be obtained prior to any study related 
procedures being performed.  
 
 Study Interventional Phase  
The study interventional phase will occur during the intraoperative period from  after 
placement of second IV line or bolus of propofol (if IV line is present prior to induction) to 
the last stimulus.  

 
  
6 
 
6 
EEG Monitoring 
EEG monitoring will start after induction and end after the last stimulus.  
Stimuli 
 At steady-state EEG SEF, two research stimuli (placement of oral pacifier and electrical 
stimulation) will be performed by the study investigator(s). The third stimulus, 
laryngoscopy—a clinically required procedure, will be performed by the anesthesia team on 
record caring for the patient.  
 
Propofol dosing 
Adjustment to propofol infusion and dosing is considered standard of care and is needed to 
achieve different anesthetic depths and SEF targets for different stimuli. As described in the 
study flowchart below, if current SEF is below target SEF, then propofol dose will be 
decreased. Conversely, if current SEF is above target SEF, then propofol dose will be 
increased. 
 
Second IV Placement 
An IV separate from the propofol infusion line will be placed in order to draw blood 
samples to evaluate propofol plasma concentration. Often the second IV will also be 
clinically indicated regardless of study status. If the second IV line is unable to be placed, a 
butterfy needle may be used to draw a single sample.  
Blood Sample Collection  
Up to three 1ml blood samples, for a total of 3ml, will be collected during the study 
interventional phase.  
3.2 Study Duration, Enrollment and Number of Sites 
 Duration of Patient Study Participation 
The study duration for each patient will be the day of the procedure during the intraoperative 
period.  
 
 Total Number of Study Sites/Total Number of Patients Projected 
The study will only be conducted at CHOP. It is expected that approximately 150 patients 
will be enrolled to produce 120 evaluable patients, 60each in the 3-12mo and 13-24mo age 
groups. 
 
3.3 Study Population 
 Inclusion Criteria 
1) Children 3 to 24 month old undergoing a procedure. 

 
  
7 
 
7 
2) Planned laryngoscopy and endotracheal intubation or laryngeal mask airway (LMA) 
placement for clinical care. 
3) Planned propofol anesthesia for anesthesia maintenance during study period. 
4) ASA < III. 
5) Muscle relaxant not indicated per planned clinical care for laryngoscopy/intubation or 
LMA. 
6) Anticipated procedure duration approximately < 2h40min 
 
 Exclusion Criteria 
1) Patients undergoing an emergency procedure. 
2) Known severe neurological disease which might result in abnormal EEG SEF. 
3) Deformities of forehead (difficult EEG sensor placement). 
4) Known difficult airway. 
5) Allergy to propofol. 
6) Attending anesthesiologist on record caring for patient plans to administer additional IV 
medication besides propofol during study phase. 
7) Currently on anti-seizure medication (might alter propofol pharmacodynamics). 
 
Patients that do not meet all of the enrollment criteria may not be enrolled. Any violations of 
these criteria must be reported in accordance with IRB Policies and Procedures.   
 
4 
STUDY PROCEDURES 
4.1 Screening Phase  
Procedures below will be performed during the screening phase.  
• 
Informed Consent/HIPAA authorization 
• 
Medical Record Review 
 
4.2 Study Interventional Phase 
 EEG Recording  
After anesthesia induction, Masimo Sedline EEG will be applied to the patient’s 
forehead and recording will continue until after the last stimulus.  
 Stimuli 
Two research stimuli: placement of oral pacifier and electrical stimulation will be performed 
by the study investigator. The third stimulus, laryngoscopy, will be performed by the 
anesthesia team on record caring for the patient. The stimulus will be performed after the 
patient has achieved steady state at target EEG SEF, as described in the flowchart below. 
The response to each of the three stimuli (Yes/No) will be recorded. Given time contraints, 
not all three stimuli may be performed on each patient. Each research stimulus may only be 

 
  
8 
 
8 
applied once to each patient. The flowchart below shows the study procedures. Details of the 
stimuli are below: 
1) Placement of oral pacifier involves placing a soft pacifier inside the patient’s mouth. 
2) Electrical stimulation is typically done to assess neuromuscular function. 
3) Laryngoscopy is done prior to intubation (placement of breathing tube) and is considered 
a clinically-required procedure for all patients. 
 
 
 
 
4.3 
Patient Completion/Withdrawal 
Parents or caregivers may withdraw the patient from the study at any time without prejudice 
to their care. They may also be discontinued from the study at the discretion of the 
responsible attending anesthesiologist on record and/or study investigator due to unforeseen 
circumstances (unable to establish IV access, lack of time, unable to achieve steady state 
SEF, etc…). The placement of the second IV will occur alongside routine clinical care. It 
will not result in additional anesthesia time as standard care is able to continue while the IV 
is being placed.  If the study investigator becomes aware of any serious, related adverse 
events after the patient completes or withdraws from the study, they will be recorded in the 
source documents and on the CRF. 
 

 
  
9 
 
9 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 
Screening and Monitoring Evaluations and Measurements 
 Medical Record Review 
• PHI: MRN, name, element of dates including birth date and service dates 
• Demographic 
• Anesthetic records 
• Medication list 
• Surgical records 
• Post operative recovery records 
• Expected procedure duration and procedure type 
• ASA status 
 
 EEG Monitoring  
The study team will assess skin integrity prior to applying the EEG sensor. After anesthesia 
induction, the Masimo EEG sensor will be placed on the forehead and connected to the EEG 
monitor. EEG monitoring for the study will continue until laryngoscopy. The Masimo EEG 
monitor will automatically calculate and display EEG SEF values.  
 Propofol Dosing  
Propofol will be administered via an infusion pump with initial dosing based on a 
published dosing table used in CHOP clinical practice (table 1).12 This table serves as a 
starting guide to dosing, ultimately EEG SEF will be used to titrate propofol dose. Propfol 
dosing adjustments to achieve target SEF are described in section 5.1.8 below. 
 Stimuli 
For this study, laryngoscopy is clinically required for anesthesia and the procedure, whereas 
electrical stimulation are often performed, but may not always be clincally required.  
Depending on time constraints, each patient may have two to three stimuli applied in 
sequence (placement of oral pacifier, electrical stimulus, and laryngoscopy). Based on 
responses to each stimulus, the SEF target and propofol dose may be adjusted for the next 

 
  
10 
 
10 
stimulus. Each stimulus may only be applied once per patient and all stimuli will be 
completed prior to intubation.  
If sevoflurane was used during anesthesia induction, then sevoflurane will need to be 
washed out prior to performing the first stimuli, to avoid residual sevoflurane’s effects on 
the brain and EEG. This can be done by turning off sevoflurane to allow the patient to expire 
the sevoflurae through breathing. Sevoflurane washout is complete when end tidal 
sevoflurane concentration < 0.2%. Propofol infusion and EEG monitoring will start prior to 
completing sevoflurane washout. 
Placement of oral pacifier  
After anesthesia induction, sevoflurane washout (if applicable), and EEG SEF at the target 
for placement of oral pacifier, an oral pacifier will be placed in the patient’s mouth. The oral 
pacifier will be withdrawn if there is a positive response (defined in section 5.1.5 ) or when 
5 seconds has elapsed.  
Electrical stimulus  
The study team will assess forearm skin integrity prior to applying the nerve stimulator 
electrodes. After sevoflurane washout (if applicable) and EEG SEF at the target for 
electrical stimulus, a nerve stimulator (Halyard EZstim, Halyard Health Inc) will be initiated 
at 50hz 30mA for up to 15 seconds.30 The electrical stimulus will stop if there is a positive 
response (defined below) or when 15 seconds has elapsed.  
Laryngoscopy  
After sevoflurane washout (if applicable) and EEG SEF at the target for laryngoscopy, 
laryngoscopy will be performed by the anesthesia team on record caring for the patient. This 
will mark the end of the stimuli interventions. If no response to laryngoscopy is elicited, the 
anesthesia team on record may choose to intubate the patient or administer additional 
medications. If a positive response to laryngoscopy is elicited, the anesthesia team on record 
may choose to stop laryngoscopy and/or administer additional medications such as 
neuromuscular relaxant. 
 
Responses to the stimuli will be recorded. The patient will be monitored closely by the study 
team for any adverse events. Study interventions will occur simultaneously with routine 
clinical anesthesia and surgical care; therefore, there will be no additional time under 
anesthesia from this study. Not every patient will have all three stimuli performed and some 
patients may have only one research stimuli performed. Study procedures will be stopped 
once all standard, clinical care preparation for surgery is completed.  
The same stimulus will not be applied twice to the same patient. The patient’s study 
involvement will conclude once laryngoscopy has been performed on the patient and blood 

 
  
11 
 
11 
draw (if applicable) has been performed. The remainder of the anesthetic will be per routine 
care.  
 
 Responses to Stimuli 
A positive response to the stimuli described above is occurrence of any of the 
following: swallowing, sucking, eye opening, facial movement, gross limb movement 
towards the source of stimulus, and additionally for laryngoscopy, breathing-holding, 
closure of vocal cords, and coughing. These responses typically occur at the subconscious 
level without causing awareness of the stimulus. Patient response (Yes/No) will be recorded 
for each stimulus applied.  
 
 Blood collection  
Before a  stimulus is applied, the SEF value and vital signs will be recorded and a 1ml blood 
sample will be obtained (not from the propofol infusion IV line). Up to three blood samples 
may be collecteds..  
 Dixon Up-Down Technique 
Using Dixon up-down technique, the current patient’s response to stimulus at a SEF 
target will determine the next patient’s SEF target for the same stimulus, thus forming the 
sequential design method. Using placement of oral pacifier as an example and SEF step size 
of 2hz, patient #1 starts at SEF target of 18hz and has a positive response to placement of 
oral pacifier. Patient #2 will have a decrement of SEF target by one step size to 16hz (18 
minus 2) for the same stimulus. If patient #2 also has a positive response to placement of 
oral pacifier, then patient #3 will have a further decrement in SEF target by one step size to 
14hz (16 minus 2). If patient #3 has a negative response to placement of oral pacifier, then 
patient #4 will increase SEF target one step to 16hz (14 plus 2). This continues until there 
are consecutive crossovers (typically six up-down-up-down…), whereby the median SEF 
and standard deviation can be calculated for the specific stimulus.24 Since each stimulus is of 
varying intensity, it’s expected that each of the 3 stimuli will have its own Dixon up-down 
calculated SEF target. 
 
 Achieving SEF target 
The EEG SEF targets will be different for each of the three stimuli (e.g., the propofol 
dose and anesthetic depth to block response to placement of oral pacifier is less than for 
electrical stimulation and laryngoscopy). Based on our clinical experience, the initial SEF 
targets for the first patient will be 20, 14, and 10hz for placement of oral pacifier, electrical 
stimulation, and laryngoscopy, respectively. For the same stimulus, the subsequent patient’s 
target SEF will be determined by the previous patient’s response to that stimulus, as 

 
  
12 
 
12 
described in the section Dixon up-down technique. After sevoflurane washout (if applicable) 
and the propofol infusion dose and SEF are constant for 5 minutes, to ensure equilibration 
between propofol brain Ce and plasma concentration, the stimulus will be applied as 
described in the section EEG vs Propofol Ce. If current SEF is higher than target SEF, 
additional propofol (0.5-2mg/kg boluses and/or 10-20% increases in propfol infusion rate) 
can be given to decrease SEF closer to target SEF. Conversely, if current SEF is lower than 
target SEF, propofol infusion rate can be decreased 10-20% or temporarily paused to 
increase SEF to target SEF.  
 
5.2 Laboratory test  
Blood samples will be sent to  Institutional Core laboratory at CHOPfor batch 
processing to measure plasma propofol concentration.   
 
5.3 Safety Evaluation 
Patient safety will be monitored by adverse events, vital signs, and patients’ response.  
 
5.4 Non-evaluable Subjects 
Non-evaluable subjects include 1) patient received IV medication other than propofol and 
midazolam from the anesthesia team during study phase, 2) unable to get EEG SEF reading 
during study phase, or 3) unable to decrease expired sevoflurane to ≤ 0.2% during study 
period.  
 
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
Three EEG SEF50 values corresponding to where 50% of patients do not respond to 1) 
placement of oral pacifier EEG SEF50, 2) electrical stimulation EEG SEF50, and 3) 
laryngoscopy EEG SEF50.  
 
6.2 Secondary Endpoints 
The propofol effect site concentration corresponding to each EEG SEF50 will be determined 
from the regression between plasma propofol concentration vs SEF recorded at the time of the 
blood draw. 
 
6.3 Statistical Methods 
 Baseline Data  
Baseline and demographic characteristics will be summarized with standard descriptive 
summaries (e.g. means and standard deviations for continuous variables such as age and 
percentages for categorical variables such as gender). 
 

 
  
13 
 
13 
 EEG SEF  
The median EEG SEF (SEF50) for a stimulus is the SEF where half the patients do not 
respond to that particular stimulus. SEF50 will be determined for each of the three stimuli for 
the 3-12 mo and 13-24 mo age groups. For each stimuli, each SEF crossover pair (Yes to No 
response or vice versa) in the Dixon’s up-down response will be treated as a SEF pair and 
the mean SEF50 and standard deviation of the SEF pairs will be determined. See figure 
below for example of Dixon’s up-down method and determination of SEF50 for 
laryngoscopy. X axis represents sequential patients #1 to #30, Y axis represent SEF levels. 
Each blue (Yes response) and red (No response) dot represent a patient. The orange bars on 
the X axis represent crossover pairs, used to calculate SEF50. 
In the laryngoscopy example below, the mean SEF50 is 8.22hz and standard deviation is 
1.83hz, derived from crossover points: 5, 9, 9, 9, 9, 9, 7, 7, 5, 7, 7, 7, 7, 11, 11, 11, 9, 9hz. 
 
 
  Propofol Ce 
The propofol plasma concentration will be determined by laboratory measurements. A 
regression curve will be determined from the plot of plasma propofol concentration vs SEF 
at the time the blood was drawn for the propofol level. At steady state, plasma propofol and 
propofol Ce are equal. The propofol Ce corresponding to each SEF50 will be calculated from 
the regression. There will be two regression curves, one for the 3-12 mo age group and the 
other for the 13-24 mo age group. See figure below for example of Propofol Ce vs SEF 
curve for one age group; x-axis is SEF and y-axis is propofol Ce. 

 
  
14 
 
14 
  
 Sample Size and Power 
Many anesthesia studies utilizing the Dixon up-down design have a sample size of 10-30 for 
each stimulus.23 Hammer et al. used the Dixon up-down method to determine the propofol 
median effective dose (ED50) to prevent movement in children undergoing gastro-
endoscope insertion with a sample size of 12.31 Endoscope insertion is a procedure similar to 
laryngoscopy. We propose a sample size of 30 for each stimulus for each age group. 
Because only one or two stimuli can be performed per patient within the proposed study 
time (e.g., placement of oral pacifier before laryngoscopy, or nerve stimulation before 
laryngoscopy), the required sample size of subjectsfor each age group needs to be up to 60, 
for a towal of 120 evaluable patients.  Two age groups are selected because of normal age-
dependent EEG changes in the first few years of life that could affect the EEG SEF.  
 
6.4 
Safety Analysis 
During the study period, adverse events (AE) are defined as:  
1- Oxygen desaturation (< 85% for more than 30 seconds). 
2- Hypotension (mean arterial pressure < 40 mmHg for 3-12 mo and < 45 mmHg for 13-24 
mo across at least two measurements). 
3- Bradycardia (HR < 60 bpm for more than 30 seconds) will be recorded for all patients.  
4- Overhead call for emergency help. 
5- Laryngospasm requiring intervention.  

 
  
15 
 
15 
 
AE incidence will be summarized along with the corresponding SEF values during the 
occurrence.  
 
7 
SAFETY MANAGEMENT 
7.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
 
7.2 Adverse Event Reporting 
Unanticipated problems related to the research involving risks to patients or others that 
occur during the course of this study (including SAEs) will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Patients. 
AEs that do not meet prompt reporting requirements will be summarized in narrative or 
other format and submitted to the IRB at the time of continuing review (if continuing 
reviews are required), or will be tracked and documented internally by the study team but 
not submitted to the IRB (if continuing reviews are not required).   
 
7.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient who has received the 
study intervention procedures: placement of oral pacifier and electrical stimulation. The 
occurrence does not necessarily have to have a causal relationship with the treatment. An 
AE can therefore be any unfavorable or unintended sign, symptom, or disease temporally 
associated with the use of study required procedure, whether or not considered related to the 
study procedure. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 
 
7.4 Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• death, 
• coma, 
• heart, lung, or brain demage,   
• requires unanticipated inpatient hospitalization or prolongation of existing 
hospitalization, 
• a persistent or significant disability/incapacity, or an important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered a 

 
  
16 
 
16 
serious adverse event when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. 
 
 Relationship of SAE to study intervention 
The relationship of each SAE to the study intervention should be characterized using one of 
the following terms in accordance with CHOP IRB Guidelines: definitely, probably, 
possibly, unlikely or unrelated.  
7.5 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse 
Events that are related to the research activity. Other unanticipated problems related to the 
research involving risk to patients or others will also be reported promptly. Written reports 
will be filed using the eIRB system and in accordance with the timeline below. External 
SAEs that are both unexpected and related to the study intervention will be reported 
promptly after the investigator receives the report.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
 
 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
 
8 
STUDY ADMINISTRATION 
8.1 Data Collection and Management 
Minimal identifiable information might be printed and recorded on paper for study eligibility 
clarification, study data collection, data validation, and consenting document. Any paper 
documents will only be accessible to approved CHOP staff and will be kept in the locked 

 
  
17 
 
17 
research office when not in use. Any un-needed paper data that has identifiable information will 
be shredded as soon as possible.  
• 
Confidentiality: A master list containing PHI and patient ID number will be kept in 
REDCap. PHI will be labled as “Identifier” in REDCap, so data could be exported 
as coded dataset for analysis.  
• 
Security: Data will be kept in the REDCap database and CHOP secure servers.  
8.2 Confidentiality 
No identifiable data will be used for future study without first obtaining IRB approval or 
determination of exemption. All data and records generated during this study will be kept 
confidential in accordance with Institutional policies and HIPAA on subject privacy and that 
the Investigator and other site personnel will not use such data and records for any purpose 
other than conducting the study. The investigator will obtain a data use agreement between 
the provider (the PI) of the data and any recipient researchers before sharing a limited 
dataset (PHI limited to dates and zip codes). 
8.3 Regulatory and Ethical Considerations 
 Data and Safety Monitoring Plan 
The study will have an independent DSMB committee: Drs. Arjunan Ganesh, Raj 
Subramanyam, and Tori Sutherland, who are not involved in this study. The DSMB 
committee will meet before every continuing review or as needed to monitor and review the 
study progress, patient safety, and the accuracy and security of the emerging data. During 
the study period, each patient will be monitored for any adverse events or safety concerns by 
investigators. Additionally, the PI will monitor and review the study progress, subject safety, 
and the accuracy and security of the emerging data. 
 
 Risk Assessment 
The assessment to support the study involving greater than minimal risk but  presenting the 
propect of direct benefit to the individual subjects to qualify for approval under 45 CFR 
§46.405. The study protocol required procedures are placement of oral pacifier, electrical 
stimulus, laryngoscopy, and blood draws from an IV.   
• Risks of placement of oral pacifier: Minimal. 
• Risks of electrical stimulation: Minimal (redness and irritation to the skin from the 
adhesive on the electrodes, which should self-resolve within 24 hours).  
• Risks of laryngoscopy: Coughing, breath-holding, vocal cord closure, and arterial 
desaturation. Laryngoscopy is a clinically necessary procedure that will be performed 
regardless of study. Patients may have increased risk of vocal cord closure because they 
will not receive a muscle relaxant for intubation, although laryngoscopy is often done 
without muscle relaxant in standard clinical care (55% of the time). Furthermore, a 
muscle relaxant for intubation is contraindicated for many patients in our study due to 

 
  
18 
 
18 
the type of procedure. Patients undergoing a procedure who are not expected to require 
muscle relaxant will be enrolled. Patients may experience temporary arterial desaturation 
during anesthesia care related to coughing and breathholding during induction, 
emergence, and recovery. Laryngoscopy is not a study-related risk and will occur 
regardless of study participation.  
• Risks of blood draws: Minimal. Blood will be collected while the patient is anesthetized. 
The investigator will adhere to the NIH "Guidelines for Limits of Blood Drawn for 
Research Purposes" and no more than 5 mL/kg will be drawn for research purposes in a 
single day. 
 
The study period occurs before the procedure and any surgical stimulation, therefore there is 
no risk associated with withholding regional anesthetic, opioids, or dexmedetomidine. 
Propofol is often given as the sole agent during the induction period. There may be a small 
risk associated with withholding muscle relaxant prior to laryngoscopy, The potential risks 
include coughing, movement, and laryngospasm, although these risks are far less with 
propofol. 
Study interventions will happen concurrenly with routine clincal care; there will be no 
additional anesthesia time. 
The risks associated with the use of EEG are no more than minimal. It is possible that the 
adhesive sensor may irritate the skin. Sensor sites will be checked for possible irritation. 
 
 Potential Benefits of Trial Participation 
There may be direct benefits to the study participants, since they will have EEG monitoring 
during the study period making them less likely to experience isoelectric EEG and 
associated hypotension. Isoelectric EEG is common in young children under anesthesia, 
63% at CHOP32 and 32% worldwide15. Isoelectric EEG is associated with intraoperative 
moderate and severe hypotension, preventable critical events that increase morbidity.33 
Indirect benefits to future patients include: 1) improved accuracy of propofol dosing in 
infants and toddlers; 2) safer propofol anesthesia care- lower incidence of hypotension from 
over-dosing, and lower incidence of insufficient anesthesia from propofol under-dosing; and 
3) better efficacy- faster emergence and recovery from less propofol over-dosing. 
 
 Risk-Benefit Assessment 
This study involves no more than a minor increase above minimal risk. There are direct 
benefits to study participants to have EEG monitoring to prevent isoelectric EEG and 
associated hypotension, and indirect benefits to future patients for preventing propofol 
under- and over-dosing. 
 

 
  
19 
 
19 
8.4 Recruitment Strategy 
Potential patients will be identified from the scheduled procedure list. Investigator will only 
approach permissible patients.  
 
8.5 Informed Consent and HIPAA Authorization 
Patients’s parent(s)/legal guardian(s) will be approached by investigator prior to the 
procedure in a private setting, such as a private exam room. The investigation team will 
make a good faith effort to obtain consent the day prior to the procedure. The primary aim, 
risks, benefits and study procedures for the study will be explained and the parent(s)/legal 
guardian(s) will have ample time and opportunity to ask questions. It will be reiterated that 
the decision to participate or decline to participate in the study will have no bearing on their 
medical care.  
 
Per institutional policy, the investigators intend to obtain electronic "written" consent via 
REDCap, the following criteria apply  
• A valid electronic signature must be obtained.  
• The patient will receive an electronic copy of completed consent and HIPAA 
authorization form by emailing from REDCap.  
If unable to obtain consent electronically, a paper copy of the consent form will be signed and 
uploaded to the study’s REDCap.  
Individuals with Limited English Proficiency  
The short form consent process will be utilized for enrollement of limited English 
proficiency patients. The investigator is familiar with the IRB's guidance on the short form 
consent process, i.e. the use of interpreters, the requirement of a witness, and the required 
signing of a study summary document and a short form consent form by the respective 
parties. If REDCap electronic consent is used for LEP patients and an in-person interpreter 
is not available, phone interpretation through Language Services Associates will be utilized 
as outlined in the Office of Research Compliance guidance and no study procedures will 
take place until all electronic signatures have been obtained.  
 
8.6 Payment to Patients/Families 
There will be no payments to families.  
 
9 
PUBLICATION 
Publication in a peer-reviewed journal will be pursued after completion of the study.  
Only aggregate data without individual identifiable information will be published.  
 

 
  
20 
 
20 
10 REFERENCES 
1. 
Brioni JD, Varughese S, Ahmed R, Bein B. A clinical review of inhalation 
anesthesia with sevoflurane: from early research to emerging topics. Journal of 
anesthesia. 2017;31(5):764-778. 
2. 
Chidambaran V, Costandi A, D’Mello A. Propofol: a review of its role in pediatric 
anesthesia and sedation. CNS drugs. 2015;29(7):543-563. 
3. 
Morse J, Hannam JA, Cortinez LI, Allegaert K, Anderson BJ. A manual propofol 
infusion regimen for neonates and infants. Pediatric Anesthesia. 2019;29(9):907-
914. 
4. 
Sepúlveda P, Cortinez L, Sáez C, Penna A, Solari S, Guerra I, Absalom AR. 
Performance evaluation of paediatric propofol pharmacokinetic models in healthy 
young children. British journal of anaesthesia. 2011;107(4):593-600. 
5. 
Oberer C, von Ungern-Sternberg BS, Frei FJ, Erb TO. Respiratory reflex responses 
of the larynx differ between sevoflurane and propofol in pediatric patients. The 
Journal of the American Society of Anesthesiologists. 2005;103(6):1142-1148. 
6. 
Chandler JR, Myers D, Mehta D, Whyte E, Groberman MK, Montgomery CJ, 
Ansermino JM. Emergence delirium in children: a randomized trial to compare total 
intravenous anesthesia with propofol and remifentanil to inhalational sevoflurane 
anesthesia. Pediatric Anesthesia. 2013;23(4):309-315. 
7. 
Sneyd J, Carr A, Byrom W, Bilski A. A meta-analysis of nausea and vomiting 
following maintenance of anaesthesia with propofol or inhalational agents. European 
Journal of Anaesthesiology| EJA. 1998;15(4):433-445. 
8. 
Sarner JB, Levine M, Davis PJ, Lerman J, Cook RD, Motoyama EK. Clinical 
characteristics of sevoflurane in children: a comparison with halothane. The Journal 
of the American Society of Anesthesiologists. 1995;82(1):38-46. 
9. 
Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in 
infants and children. The Journal of the American Society of Anesthesiologists. 
1994;80(4):814-824. 
10. 
Kim T, Niklewski P, Martin J, Obara S, Egan T. Enhancing a sedation score to 
include truly noxious stimulation: the Extended Observer's Assessment of Alertness 
and Sedation (EOAA/S). BJA: British Journal of Anaesthesia. 2015;115(4):569-577. 
11. 
Fuentes R, Cortínez I, Ibacache M, Concha M, Muñoz H. Propofol concentration to 
induce general anesthesia in children aged 3–11 years with the Kataria effect‐site 
model. Pediatric Anesthesia. 2015;25(6):554-559. 
12. 
Xu T, Kurth CD, Yuan I, Vutskits L, Zhu T. An approach to using pharmacokinetics 
and electroencephalography for propofol anesthesia for surgery in infants. Pediatric 
Anesthesia. 2020;30(12):1299-1307. 
13. 
Purdon PL, Sampson A, Pavone KJ, Brown EN. Clinical Electroencephalography for 
Anesthesiologists: Part I: Background and Basic Signatures. Anesthesiology. 
2015;123(4):937-960. 
14. 
Chan MT, Hedrick TL, Egan TD, García PS, Koch S, Purdon PL, Ramsay MA, 
Miller TE, McEvoy MD, Gan TJ. American Society for Enhanced Recovery and 
Perioperative Quality Initiative joint consensus statement on the role of 

 
  
21 
 
21 
neuromonitoring in perioperative outcomes: electroencephalography. Anesthesia & 
Analgesia. 2020;130(5):1278-1291. 
15. 
Yuan I, Xu T, Skowno J, Zhang B, Davidson A, von Ungern-Sternberg BS, 
Sommerfield D, Zhang J, Song X, Zhang M. Isoelectric Electroencephalography in 
Infants and Toddlers During Anesthesia for Surgery-an International Observational 
Study. Anesthesiology. 2022. 
16. 
FDA. Propofol FDA 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019627s062lbl.pdf. 
Accessed. 
17. 
Yuan I, Xu T, Kurth CD. Using Electroencephalography (EEG) to Guide Propofol 
and Sevoflurane Dosing in Pediatric Anesthesia. Anesthesiology Clinics. 
2020;38(3):709-725. 
18. 
Hayashi K, Shigemi K, Sawa T. Neonatal electroencephalography shows low 
sensitivity to anesthesia. Neuroscience letters. 2012;517(2):87-91. 
19. 
Davidson AJ, Wong A, Knottenbelt G, Sheppard S, Donath S, Frawley G. MAC‐
awake of sevoflurane in children. Pediatric Anesthesia. 2008;18(8):702-707. 
20. 
Zbinden A, Maggiorini M, Petersen-Felix S, Lauber R, Thomson D, Minder C. 
Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen 
anesthesia I. Motor reactions. Anesthesiology: The Journal of the American Society 
of Anesthesiologists. 1994;80(2):253-260. 
21. 
Inomata S, Kihara S, Yaguchi Y, Baba Y, Kohda Y, Toyooka H. Reduction in 
standard MAC and MAC for intubation after clonidine premedication in children. 
British journal of anaesthesia. 2000;85(5):700-704. 
22. 
Dixon W. The up-and-down method for small samples. Journal of the American 
Statistical Association. 1965;60(312):967-978. 
23. 
Pace NL, Stylianou MP, Warltier DC. Advances in and limitations of up-and-down 
methodology: a precis of clinical use, study design, and dose estimation in anesthesia 
research. Anesthesiology. 2007;107(1):144-152. 
24. 
Görges M, Zhou G, Brant R, Ansermino JM. Sequential allocation trial design in 
anesthesia: an introduction to methods, modeling, and clinical applications. Pediatric 
Anesthesia. 2017;27(3):240-247. 
25. 
Kataria BK, Ved SA, Nicodemus HF, Hoy GR, Lea D, Dubois MY, Mandema JW, 
Shafer SL. The pharmacokinetics of propofol in children using three different data 
analysis approaches. The Journal of the American Society of Anesthesiologists. 
1994;80(1):104-122. 
26. 
Coppens MJ, Eleveld DJ, Proost JH, Marks LA, Van Bocxlaer JF, Vereecke H, 
Absalom AR, Struys MM. An evaluation of using population pharmacokinetic 
models to estimate pharmacodynamic parameters for propofol and bispectral index 
in children. The Journal of the American Society of Anesthesiologists. 
2011;115(1):83-93. 
27. 
Absalom A, Amutike D, Lal A, White M, Kenny G. Accuracy of the ‘Paedfusor’in 
children undergoing cardiac surgery or catheterization. British Journal of 
Anaesthesia. 2003;91(4):507-513. 

 
  
22 
 
22 
28. 
Rigouzzo A, Girault L, Louvet N, Servin F, De-Smet T, Piat V, Seeman R, Murat I, 
Constant I. The relationship between bispectral index and propofol during target-
controlled infusion anesthesia: a comparative study between children and young 
adults. Anesthesia & Analgesia. 2008;106(4):1109-1116. 
29. 
Sahinovic MM, Struys MM, Absalom AR. Clinical pharmacokinetics and 
pharmacodynamics of propofol. Clinical pharmacokinetics. 2018;57(12):1539-1558. 
30. 
Olbrecht VA, Jiang Y, Viola L, Walter CM, Liu H, Kurth CD. Characterization of 
the functional near‐infrared spectroscopy response to nociception in a pediatric 
population. Pediatric Anesthesia. 2018;28(2):103-111. 
31. 
Hammer GB, Litalien C, Wellis V, Drover DR. Determination of the median 
effective concentration (EC50) of propofol during oesophagogastroduodenoscopy in 
children. Pediatric Anesthesia. 2001;11(5):549-553. 
32. 
Yuan I, Landis WP, Topjian AA, Abend NS, Lang S-S, Huh JW, Kirschen MP, 
Mensinger JL, Zhang B, Kurth CD. Prevalence of isoelectric electroencephalography 
events in infants and young children undergoing general anesthesia. Anesthesia & 
Analgesia. 2020;130(2):462-471. 
33. 
Disma N, Veyckemans F, Virag K, Hansen TG, Becke K, Harlet P, Vutskits L, 
Walker SM, de Graaff JC, Zielinska M. Morbidity and mortality after anaesthesia in 
early life: results of the European prospective multicentre observational study, 
neonate and children audit of anaesthesia practice in Europe (NECTARINE). British 
Journal of Anaesthesia. 2021;126(6):1157-1172.