Bispectral Index and End-Tidal Anesthetic Gas Concentration in Pediatric Patients Undergoing Sevoflurane Anesthesia (BTIGER)
Phase: NA
Conditions: Anesthesia
Sponsor: Medtronic - MITG

Bispectral Index and End Tidal Anesthetic Gas Concentration in Pediatric 
Patients undergoing Sevoflurane Anesthesia Clinical Investigation Plan  
 
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f
 
Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  Bispectral Index and End-Tidal Anesthetic Gas 
Concentration in Pediatric Patients undergoing 
Sevoflurane Anesthesia (BTIGER) 
Clinical Investigation Plan Identifier MDT20032BTIGER 
Study Product Name BIS Complete Monitoring System 
Sponsor/Local Sponsor Medtronic 
Patient Monitoring & Respiratory Interventions  
6135 Gunbarrel Avenue, 
Boulder, CO 80301 
U.S.A. 
Document Version 4.1 
Version Date 23 JAN 2023 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 
 
 

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1 Table of Contents  
 
1 
Table of Contents .......................................................................................................................................... 2 
2. 
Glossary......................................................................................................................................................... 7 
3. 
Synopsis ........................................................................................................................................................ 9 
4. 
Introduction ................................................................................................................................................ 21 
4.1. Background ..................................................................................................................................................... 21 
4.1.1. 
Basics of Anesthesia & Anesthetics ....................................................................................... 21 
4.1.2. 
EEG Monitoring in Anesthesia ............................................................................................... 21 
4.1.3. 
BIS Monitoring in Pediatric Populations ............................................................................... 22 
4.2. Purpose ........................................................................................................................................................... 28 
5. 
Objectives and/or Endpoints ....................................................................................................................... 29 
5.1. Objectives ....................................................................................................................................................... 29 
5.1.1. 
Primary Objective(s) .............................................................................................................. 29 
5.2. Endpoints ........................................................................................................................................................ 29 
5.2.1. 
Primary Endpoint(s) .............................................................................................................. 29 
5.2.2. 
Secondary Endpoint(s) .......................................................................................................... 29 
6. 
Study Design ................................................................................................................................................ 30 
6.1. Duration .......................................................................................................................................................... 30 
6.2. Rationale ......................................................................................................................................................... 30 
7. 
Product Description ..................................................................................................................................... 31 
7.1. General ........................................................................................................................................................... 31 
7.2. Manufacturer ................................................................................................................................................. 31 
7.3. Packaging ........................................................................................................................................................ 32 
7.4. Intended Population ....................................................................................................................................... 32 
7.4.1. 
BIS™ Complete Monitoring System Indications for Use .......................................................................... 32 
7.4.2. 
Pulse Oximetry System Indications for Use ............................................................................................. 32 
7.5. Equipment ...................................................................................................................................................... 32 
7.5.1. 
BIS™ Complete Monitoring System....................................................................................... 32 

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7.5.1.1. 
BIS™ Complete Monitor .................................................................................................... 33 
BISx™ Modules .................................................................................................................................... 33 
Patient Interface Cable ....................................................................................................................... 34 
BIS™ Sensor ......................................................................................................................................... 34 
Nellcor™ N-600x Pulse Oximetry System ............................................................................................ 35 
7.6. Product Use .................................................................................................................................................... 36 
7.7. Product Training Requirements ...................................................................................................................... 37 
7.8. Product Receipt and Tracking ......................................................................................................................... 37 
7.9. Product Storage .............................................................................................................................................. 37 
7.10. Product Return ............................................................................................................................................... 37 
7.11. Product Accountability ................................................................................................................................... 37 
8. 
Study Site Requirements ............................................................................................................................. 38 
8.1 Investigator / Investigation Study Site Selection ............................................................................................ 38 
8.2 Study Site Activation ....................................................................................................................................... 38 
8.3 Role of the Sponsor Representatives ............................................................................................................. 39 
9. 
Selection of Subjects ................................................................................................................................... 39 
9.1. Study Population ............................................................................................................................................ 39 
9.2. Subject Enrollment ......................................................................................................................................... 40 
 Inclusion Criteria ............................................................................................................................................. 40 
 Exclusion Criteria ............................................................................................................................................ 40 
10. 
Study Procedures ..................................................................................................................................... 41 
10.1 Schedule of Events ......................................................................................................................................... 41 
10.2 Data Collection ............................................................................................................................................... 41 
10.3 Subject Screening ........................................................................................................................................... 43 
10.4 Prior and Concomitant Medications/Therapies ............................................................................................. 43 
10.5 Subject Consent .............................................................................................................................................. 43 
10.6 Enrollment ...................................................................................................................................................... 44 
10.7 Baseline .......................................................................................................................................................... 45 
10.8 Randomization and Treatment Assignment ................................................................................................... 45 
10.9 Surgical Procedure and Data Collection ......................................................................................................... 45 
10.9.1 
Prior to Induction ..................................................................................................................................... 45 

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10.9.2 
Induction .................................................................................................................................................. 46 
10.9.3 
Maintenance ............................................................................................................................................ 47 
10.9.4 
Monitoring and Cardiovascular Variables ................................................................................................ 48 
10.9.5 
Event Markers and Assessments ............................................................................................................. 48 
10.9.6 
Recovery .................................................................................................................................................. 50 
10.9.7 
Safety Monitoring .................................................................................................................................... 51 
 
Assessment of Efficacy ............................................................................................................................. 51 
10.11 
Assessment of Safety ............................................................................................................................... 51 
10.12 
Recording Data ........................................................................................................................................ 51 
10.13 
Deviation Handling .................................................................................................................................. 52 
10.14 
Subject Exit, Withdrawal or Discontinuation ........................................................................................... 53 
10.14.1 
Study Exit ........................................................................................................................... 54 
10.14.2 
Subject Chooses to Exit (i.e. Revokes Consent) ................................................................. 54 
10.14.3 
Investigator Withdraws Subject ........................................................................................ 55 
11. 
Risks and Benefits .................................................................................................................................... 55 
11.1. Potential Risks ................................................................................................................................................ 55 
11.1.1 
BIS™ Sensor Risks............................................................................................................... 55 
11.1.2 
BIS™ Monitoring System Risks ........................................................................................... 55 
11.1.3 
Pulse and Tissue Oximetry Sensor ..................................................................................... 56 
11.1.4 
General Anesthetics ........................................................................................................... 56 
11.2. Potential Benefits ........................................................................................................................................... 57 
11.3. Risk-Benefit Rationale .................................................................................................................................... 57 
11.4. Risk Determination ......................................................................................................................................... 57 
12. 
Adverse Events and Device Deficiencies ................................................................................................... 58 
12.1 Adverse Events ................................................................................................................................................ 58 
 Reporting of Adverse Events .......................................................................................................................... 60 
12.2.1 
Adverse Event and Device Deficiency Classification.......................................................... 61 
12.2.2 
Adverse Event and Device Deficiency Reporting Requirements ....................................... 61 
 Foreseeable AE or SAE .................................................................................................................................... 63 
12.3.1 
Surgical Procedure ............................................................................................................. 63 

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12.3.2 
Anesthesia Management Adverse Events ......................................................................... 63 
12.3.3 
BIS™ Sensor ....................................................................................................................... 64 
12.3.4 
Adverse Events Reported in Literature ............................................................................. 64 
 Product Complaint Reporting ......................................................................................................................... 64 
12.5 Device Deficiency ............................................................................................................................................ 65 
13. 
Data Review Committees ......................................................................................................................... 65 
13.1 Clinical Events Committee Review .................................................................................................................. 65 
14. 
Statistical Design and Methods ................................................................................................................ 65 
14.1 General Aspects of Analysis ............................................................................................................................ 66 
14.2 Sample Size Determination ............................................................................................................................. 67 
15. 
Ethics ........................................................................................................................................................ 67 
15.1. Statement(s) of Compliance ........................................................................................................................... 67 
16. 
Study Administration ............................................................................................................................... 68 
16.1. Monitoring ...................................................................................................................................................... 68 
16.1.1 Monitoring Visits ...................................................................................................................... 68 
16.2. Data Management .......................................................................................................................................... 69 
16.3. Direct Access to Source Data/Documents ...................................................................................................... 70 
16.4. Confidentiality ................................................................................................................................................ 71 
16.5. Liability ........................................................................................................................................................... 71 
16.6. CIP Amendments ............................................................................................................................................ 71 
16.7. Record Retention ............................................................................................................................................ 71 
16.7.1 
Investigator Records .......................................................................................................... 72 
16.7.2 
Sponsor Records ................................................................................................................ 73 
16.8. Reporting Requirements ................................................................................................................................ 74 
16.8.1. 
Investigator Reports .......................................................................................................... 74 
16.8.2. 
Sponsor Reports ................................................................................................................ 74 
16.9. Publication and Use of Information................................................................................................................ 75 
16.9.1. 
Publication Committee ...................................................................................................... 75 
16.9.2. 
Management of Primary, Secondary and Ancillary Publications ...................................... 75 
16.9.3. 
Criteria for Determining Authorship.................................................................................. 76 

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16.9.4. 
Transparency ..................................................................................................................... 76 
16.10. 
Suspension or Early Termination ............................................................................................................. 77 
17. 
References ............................................................................................................................................... 78 
18. 
Appendices ............................................................................................................................................... 79 
19. 
Version History ......................................................................................................................................... 81 
 
 
 

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2. Glossary     
Term 
Definition 
ADE 
Adverse Device Effect 
AE 
Adverse Event  
ASA 
American Society of Anesthesiology 
BIS™ 
Bispectral Index (BIS) technology monitoring uses processed 
EEG signals to measure sedation depth based on the level of 
consciousness  
CFR 
Code of Federal Regulation 
CIP 
Clinical Investigation Plan 
CNS 
Central Nervous System 
CO2 
Carbon Dioxide. It can be measured with a capnograph, a 
device that measures the concentration of carbon dioxide 
from each inspired and expired breath. Gases are collected 
with a non-invasive side stream from the inhaled and 
exhaled gases of the subject. Capnograph outputs numeric 
values and waveforms of the fractioned concentration of 
CO2 of each breath 
CRF 
Case Report Form 
CTA 
Clinical Trial Agreement 
CV 
Curriculum Vitae 
DD 
Device Deficiency 
DoH 
Declaration of Helsinki 
DTL 
Delegated Task List 
ECG 
Electrocardiogram. A diagnostic tool that measures and 
records the electrical activity of the heart 
eCRF 
Electronic Case Report Form 
ED 
Effective dose 
EDC 
Electronic Data Capture. Electronic systems where the data 
are collected through the eCRF (Oracle Clinical). May also be 
referred to as RDC (Remote Data Capture). 
EEG 
Electroencephalogram 

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Term 
Definition 
ET 
End-tidal concentration 
EMR 
Electronic Medical Record 
EtCO2 
End-tidal Carbon Dioxide. The value of exhaled carbon 
dioxide displayed by the capnograph device 
FD 
Financial Disclosure 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
LMA 
Laryngeal mask 
LOC 
Level of consciousness 
NSR 
Non-Significant Risk 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PIC 
Patient Interface Cable 
PK/PD 
Pharmacokinetics and pharmacodynamics 
RA 
Regulatory Authority 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SpO2 
A non-invasive spectroscopic estimate of arterial oxygen 
saturation measured transcutaneously by a pulse oximeter 

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Term 
Definition 
SOC 
Standard Of Care 
SOP 
Standard Operating Procedures 
SQI 
Signal Quality Index 
UADE 
Unanticipated Adverse Device Effect 
3. Synopsis 
Title 
Bispectral Index and End Tidal Anesthetic Gas Concentration in 
Pediatric Patients undergoing Sevoflurane Anesthesia (BTIGER) 
Clinical Study Type 
Post-Market Pivotal /IDE Study 
Product Name 
BIS™ Complete Monitoring System  
Sponsor  
Medtronic,  
Patient Monitoring & Respiratory Interventions  
6135 Gunbarrel Avenue 
Boulder, CO 80301 
Indication under 
investigation  
Intended for use in pediatric patients (4 years old and above) 
Investigation Purpose 
The purpose of this study is to investigate the relationship between 
BIS™ values including EEG profile and anesthetic agents in the 
pediatric population 
Product Status 
BIS™ is commercially available in the United States  
Primary Objective(s) and/or 
Endpoint(s)s 
Primary objective: To characterize BIS™ performance with the 
anesthetic agent in pediatric patients ages 4 to 18 years  
Primary endpoint: The end‑tidal sevoflurane concentration in both 
patient groups acquired during maintenance of anesthesia. The study 
will be considered a success if the primary objective, achieving 
statistical and clinical significance in obtaining the end-tidal 
sevoflurane concentration during maintenance in both patient 
groups, is achieved.  
Secondary Objective(s) 
and/or Endpoint(s) 
Secondary endpoint(s):  
• 
Recovery assessments in patients receiving monitoring 
compared to standard anesthetic practice (instructions 
for collection contained in Study Procedures and 
Assessments): 

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• 
Emergence 
• 
Emergence is defined as the time when any of the 
following first occurred: 
• 
Eyes open spontaneously 
• 
Crying or phonating 
• 
Purposeful movements 
• 
PACU discharge readiness using Modified Aldrete Score 
[15,16] 
• 
Anesthesia Airway Management (AAM)  will be noted: 
o Awake and Deep Extubation (endotracheal tube 
(EET) vs. laryngeal mask airway (LMA) 
o Airway reflexes (e.g., coughing, choking, 
laryngospasm) 
Additional/Exploratory Endpoints: 
• 
Clinical Anesthesia Assessment, recorded as the incidence of 
movements, grimacing, eye opening, tearing, sweating, 
mydriasis and cardiovascular changes while undergoing 
anesthesia 
• 
Pediatric Anesthesia Emergence Delirium (PAED) 
• 
Wong-Baker FACES Pain Rating Score 
Study Design 
This is a multi-center, prospective, observational, non-invasive, 
randomized controlled study to collect data to compare the 
performance of standard practice (SP) group with the BIS™ monitoring 
(BIS) group. Pediatric patients between the ages of 4 to 18 years 
undergoing routine sevoflurane general anesthesia with an expected 
maintenance duration of greater than 30 minutes will be recruited. If 
the maintenance duration is less than 25 minutes, the data will 
continue to be collected, but will not be included in the data analysis 
and the subject will be replaced with an additional subject. General 
surgeries 
including 
abdominal, 
urological, 
orthopedic, 
ophthalmological or other procedures approved by the Medtronic 
study team with an American Society of Anesthesiologists physical 
status of I - III. Children will be recruited from the preoperative clinic 
and will be divided into three age groups  
 
• 
4 to 8 years 
• 
9 to 12 years  

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• 
13 to 18 years 
A training group comprising of the first 2 - 4 subjects at each site will 
be enrolled to train the site team on the new technology and to 
determine the quality of data collection prior to randomization. 
Afterward, randomization will proceed based on the Sponsor’s 
assessment of data quality.  
 
For the BIS™ group, sevoflurane will be titrated to achieve a target 
BIS™ value of 45 – 60 during maintenance of anesthesia and a target 
BIS™ value of 60 – 75 beginning at the start of skin closure.  In order to 
protect against inadequate or excessive anesthesia in the BIS™ guided 
group, the subject will be assessed approximately every 5 minutes for 
signs of anesthesia. In the event of hypertension and/or tachycardia 
(>20% above baseline) unexplained by surgical manipulation and or 
signs of autonomic or somatic responses (e.g., diaphoresis, movement) 
an additional dose of opioid will be administered. If that does not 
resolve the situation, then the anesthesiologist may alter the 
anesthetic concentration outside the BIS™ guidelines to assure 
adequate anesthesia. In the event of hypotension and/or bradycardia 
(>20% below baseline), fluids and/or vasopressor will be administered. 
If that does not resolve the situation, then the anesthesiologist may 
alter the anesthetic concentration outside the BIS™ guidelines.   
Subjects with BIS™ values that are outside of the specified range of 45 
– 60 during maintenance of anesthesia for >35% of the maintenance 
duration will be considered a protocol deviation and the subject will be 
excluded from the final data analysis. The subject will be replaced by 
an additional enrolled subject. The excluded subject will continue to be 
monitored for any safety events and the clinician will ensure medical 
care is provided for any safety event that occurs. Data from excluded 
subjects will be acknowledged in the final study report but will not be 
included in the primary statistical analysis.  The exception to this 
exclusion is any data that is outside of the specified range of 45 – 60 as 
a result of the anesthesiologist titrating sevoflurane as a result of 
clinical signs or cardiovascular changes defined above. The end-tidal 
sevoflurane concentration will be continuously recorded. Fentanyl or 
morphine will be administered at the discretion of the anesthesiologist, 
for example, 1.5 mcg/kg at induction and 0.75 mcg/kg every 30 minutes 
in accordance with usual clinical indications.  
 
For the SP group, sevoflurane, fentanyl, propofol, and morphine will 
be administered at the discretion of the anesthesiologist for example, 
fentanyl and morphine at 1.5 mcg/kg at induction and 0.75 mcg/kg 
every 30 minutes in accordance with usual clinical indications.   

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Randomization 
Subjects will be randomized 1:1 within each age group and each site 
to one of the two groups, standard practice (SP) or BIS™ (BIS) groups. 
Sample Size 
The first 2 - 4 subjects at each site will be enrolled to train the site 
team on the new technology and to determine the quality of data 
collection prior to randomization (n = 16-32). They will not be 
randomized and will not be included in the final analysis. For the 
analysis, a minimum of 36 subjects are required in each age group (18 
per treatment group) for a minimum of 108 qualifying data sets.  
Subjects with non-qualifying data sets will be rejected and replaced 
with a newly randomized subject. This sample size was independently 
powered for each of the 3 age groups based on data from a previously 
published study conducted by Emory University. 
Planned number of sites 
Eight investigational sites in the US 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
1) Pediatric Subjects (ASA PS I or II or III) aged: 4 years to 18 years 
scheduled for procedures with sedation where the process of 
assessment will not interfere with the procedure, progress, or 
patient care 
Exclusion Criteria:  
1) Has severe contact allergies that may cause a reaction to 
standard adhesive materials found in pulse oximetry sensors, 
ECG electrodes, respiration monitor electrodes, or other 
medical sensors  
2) Known neurological disorder (e.g., epilepsy, the presence of a 
brain tumor, a history of brain surgery, hydrocephalic 
disorders, depression needing treatment with anti-depressive 
drugs, a history of brain trauma, hemiplegia, demyelinating 
disorders, cerebral palsy, congenital anomalies of the brain or 
spinal cord, or other known neurologic disorders)  
3) Severe developmental delay per assessment of investigator or 
report of parent/guardian 
4) Airway abnormalities 
5) Pregnancy; subjects of childbearing potential will have a urine 
screen for pregnancy before surgery 
6) If the process of assessment will interfere with the procedure 
or the progress of the procedure 
7) Taking psychoactive medications 

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8) Taking any medications that may have an impact on the 
Central Nervous System (CNS) 
9) Planned use of any regional anesthesia; a local field block is 
not included in this exclusion and can be used at the 
discretion of the anesthesia provider 
10) Planned use of dexmedetomidine (Precedex) 
11) Refusal to participate in the study 
Study Procedures and 
Assessments 
BIS™ Group: 
Baseline/Enrollment Visit: 
• 
Informed Consent 
• 
Review of Inclusion/Exclusion 
• 
Demographics 
• 
Medical History 
• 
Pre-operative vitals obtained in pre-operative holding 
Procedure: 
• 
Randomization: Prior to Procedure 
• 
Induction and Maintenance: 
• 
BIS™ sensor positioning and validation of appropriate 
impedance of electrodes 
• 
Clinical Anesthesia Assessment including incidence of: 
• 
Movement 
• 
Grimacing 
• 
Eye opening 
• 
Tearing 
• 
Sweating 
• 
Mydriasis 
• 
Cardiovascular changes  
• 
End of Procedure: 
• 
Collection of BIS™ sensor placement, monitoring of 
cardiovascular variables, event markers and 
assessments 
• 
Recovery: 

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• 
Anesthesia Airway management 
• 
Collection of incidents of post- op nausea 
• 
Pediatric Anesthesia Emergence Delirium (PAED) 
• 
Wong-Baker FACES Pain Rating Score when subject is 
awake 
• 
Time of PACU Discharge 
SP Group: 
Baseline/Enrollment Visit: 
• 
Informed Consent 
• 
Review of Inclusion/Exclusion 
• 
Demographics 
• 
Medical History 
• 
Pre-operative vitals obtained in pre-operative holding 
Procedure: 
• 
Randomization: Prior to Procedure 
• 
Induction and Maintenance: 
• 
BIS™ sensor positioning and validation of appropriate 
impedance of electrodes 
• 
Clinical Anesthesia Assessment including incidence of: 
• 
Movement 
• 
Grimacing 
• 
Eye opening 
• 
Tearing 
• 
Sweating 
• 
Mydriasis 
• 
Cardiovascular changes  
• 
BIS™ monitor concealing: done to ensure that the 
clinician is blinded to the BIS™ values and that the 
BIS™ value is not used to guide the conduct of the 
anesthetic. The signal quality index (SQI) number will 
be visible to the anesthesiologist during the case to 
capture a good quality signal. The details on SQI 
monitoring will be provided to the study site. 

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• 
End of Procedure: 
• 
Collection of BIS™ sensor placement, monitoring of 
cardiovascular variables, event markers and 
assessments 
• 
Recovery: 
• 
Anesthesia Airway management 
• 
Collection of incidents of post- op nausea 
• 
Pediatric Anesthesia Emergence Delirium (PAED) 
• 
Wong-Baker FACES Pain Rating Score when subject is 
awake 
• 
Time of PACU Discharge 
Prior to induction 
The subjects will be taken into the operating room, and anesthesia 
delivery system will be applied per institutional guidance. Prior to the 
induction of anesthesia, all subjects will have an age-appropriate BIS™ 
sensor applied. The clinician will select the appropriate BIS™ pediatric 
or BIS™ QUATRO sensor based on the size and space available on the 
subject's forehead. The sensor will be placed on the forehead per the 
IFU recommendation. If the patient is not cooperative when awake, the 
BIS™ sensor will be placed after adequate sedation has been achieved 
with the use of pre-medication drugs. The choice of pre-medication, 
dose, and time of administration will be determined by the site 
anesthesiologist and will not be altered for this study, but the use of 
these drugs will be recorded on the eCRFs.  
 
In addition, an age-appropriate pulse oximeter sensor (reference 7.5.1) 
will be applied to the patient per sensor IFU. A left or right index finger 
is the preferred sensor site. Alternatively, the sensors can be applied to 
a smaller finger, thumb, or big toe. The sensor type, position, and side 
will be recorded on the eCRFs. 
 
Monitoring and Cardiovascular Variables 
Pulse 
oximeter, 
non-invasive 
blood 
pressure 
(NIBP), 
electrocardiography, and skin temperature will be collected per 
institutional guidance but are not mandated per the protocol. The 
standard monitoring procedures will be conducted per institutional 
recommendation. The de-identified digital copies of these files will be 
provided to Medtronic as available.   

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Pre-surgical Cardiovascular variables (heart rate [HR]; systolic and 
diastolic blood pressure [BP] including hypotension; oxygen saturation; 
and temperature), and the BIS™ value (for the BIS™ group) will be 
recorded at baseline preferably before administering any pre-
medication or sedatives. Cardiovascular variables will be monitored 
during the surgery, and any abnormal hemodynamic parameters and 
times will be noted. The de-identified digital copies of these files will 
be provided to Medtronic as available.   
 
Induction 
Anesthesia will be induced with sevoflurane alone, or a combination of 
sevoflurane and nitrous oxide (N2O) in 100% oxygen for both groups. If 
nitrous oxide is used, it will be discontinued after the placement of a 
tracheal tube or laryngeal mask (LMA), or another airway 
management. If necessary, a neuromuscular blocking agent will be 
used to facilitate endotracheal intubation. The choice of induction 
medication, dose, and time of administration will be determined by the 
site anesthesiologist and will not be altered for this study, but the use 
of these drugs will be recorded on the eCRFs.  If the subject is in need 
of a nerve block for pain management following the procedure, this 
block should be placed once skin closure is complete and prior to 
extubation. This block cannot be placed prior to skin closure. Subjects 
with the planned use of any regional anesthesia are excluded from this 
study, however if a caudal block becomes necessary for the subject 
during the course of the surgical procedure, data will continue to be 
collected on the subject, however the data will not be included in the 
data analysis and the subject will be replaced by an additional enrolled 
subject. The use of dexmedetomidine (Precedex) is prohibited from 
being used in this study. If it becomes necessary to use this medication 
during the course of the surgical procedure, data will continue to be 
collected on the subject, however the data will not be included in the 
data analysis and the subject will be replaced by an additional enrolled 
subject. 
 
Maintenance anesthesia 
In the SP group, sevoflurane, fentanyl, and morphine administration 
will be at the discretion of the anesthesiologist, for example, fentanyl 

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and morphine 1.5 mcg/kg at induction and 0.75 mcg/kg every 30 
minutes, using clinical signs and cardiovascular changes to adjust 
anesthetic concentration.  
 
In the BIS™ group, fentanyl and morphine administration will be at the 
discretion of the anesthesiologist, for example, fentanyl and morphine 
1.5 mcg/kg at induction and 0.75 mcg/kg every 30 minutes, using 
clinical signs and cardiovascular changes, however sevoflurane will be 
adjusted to achieve a target BIS™ values of 45 – 60 during maintenance 
of anesthesia and BIS™ values of 60 – 75 beginning of skin closure.  
Subjects with BIS™ values that are outside of the specified range of 45 
– 60 during maintenance of anesthesia for >35% of the maintenance 
duration will be considered a protocol deviation and the subject will be 
excluded from the final data analysis and will be replaced by an 
additional subject. The excluded subject will continue to be monitored 
for any safety events and the clinical will ensure that medical care is 
provided should a safety event occur. Data from the excluded subject 
will be acknowledged in the final study report but will not be included 
in the primary statistical analysis. The exception to this exclusion is any 
data that is outside of the specified range of 45 – 60 as a result of the 
anesthesiologist titrating medications as a result of clinical signs or 
cardiovascular changes defined above.  Additionally, data points will be 
excluded if significant artifact is present or if the sevoflurane 
concentration or BIS™ value is missing.   
 
At the completion of the surgery, and after confirmation of the return 
of neuromuscular function, sevoflurane will be discontinued, and 
discontinuation time will be recorded, and as applicable, extubation 
will be performed when the patients demonstrate the purposeful 
movement, facial grimace, or eye-opening to jaw thrust.  
 
Event Markers and Assessments 
During the case, the time of events (for example start of induction, LOC, 
airway management /intubation (as applicable), the start of the 
procedure, incision, N2O off (as applicable), sevoflurane off, extubation 
(as applicable), eye-opening, end of the procedure, move to PACU, and 
PACU discharge readiness) will be recorded. 
 

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The end-tidal anesthetic gas concentration will be time-locked to the 
BIS™ system recordings. End-tidal sevoflurane, oxygen, and nitrous 
oxide concentrations will be downloaded from the anesthetic 
monitoring device, and de-identified digital copies will be provided to 
Medtronic. 
 
Time and values of BIS™, ETSEVO concentration (%) and other 
medication, FiO2(%) and EtO2(%), EtCO2(%) will be recorded at the 
following time intervals: 
• 
Baseline  
• 
Study start 
• 
At IV placement, as applicable 
• 
Start of induction 
• 
Start of N2O, as applicable 
• 
Start of sevoflurane 
• 
Anesthesia Airway Management (AAM)  
• 
AAM change (including type of AAM) 
• 
At any airway reflex (coughing, choking, layngospasm) 
• 
Every 15 min after airway management 
• 
At all medication administration (as applicable) 
• 
N2O off (as applicable) 
• 
Start of the surgery/procedure 
• 
Skin incision, if applicable 
• 
End of surgery/procedure (or skin dressing or cast or 
splint applied or abdominal block)  
• 
Skin closure, if applicable 
• 
Sevoflurane off 
• 
Termination of all anesthesia 
• 
Extubation 
• 
Physician Awakening subject, if applicable 
• 
Time of emergence (if occurs in OR) 
• 
End of study (removal of device)  

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• 
15 min post dexmedetomidine administration, if 
applicable 
• 
Time moved to PACU 
 
Recovery Assessments  
Subject recovery will be observed continuously after the termination 
of anesthesia for presence of coughing, choking, laryngospasms, and 
emergence. Emergence is defined as the time when any of the 
following first occurred:  
• 
eyes open spontaneously,  
• 
crying or phonating, or  
• 
purposeful movements.  
 
 The time of emergence, time subject moved to PACU, and time of 
readiness for discharge will be recorded. The time of these 
assessments will be captured in medical records, source, and 
recorded on the eCRFs. 
 
All subjects will be assessed at 15-minute intervals beginning at 
anesthesia termination: 
• 
Vitals Signs 
• 
Pediatric Anesthesia Emergence Delirium (PAED)  
• 
Wong-Baker FACES Pain Scale (when subject is awake) 
• 
PACU discharge readiness - Modified Aldrete Score  
Safety Assessments 
This is a prospective, randomized, controlled study where the only 
change in routine management is the placement of the BIS™ monitor 
probe on the forehead. The choice of sedative drugs, dose, and route 
of administration will be based on clinical indications as judged by the 
attending Anesthesiologist, and it will not be changed for the study.  
 
The BIS™ monitor will not be used in situations where the placement 
of the probe will interfere with a procedure, cause scan artifacts, or 
where the presence of a metal monitor is contraindicated (e.g., MRI 
scans). Therefore, we believe there is only a minimal increase in risks 
from participating in the study. This risk relates to the possibility of 
developing irritation to the skin at the site of placement.  

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Subjects will be monitored for Adverse Events, Serious Adverse 
Events, and Device-Related Adverse Events from BIS™ sensor 
applications throughout the BIS™ sensor removal. 
 Statistics 
Standard demographic information and baseline characteristics will be 
summarized using descriptive statistics. For safety assessments, 
adverse events (AEs) will be summarized using frequency counts and 
percentages. Descriptive statistics will be provided by severity and 
relationship as needed.  
The primary analysis will be based on all evaluable data (excluding 
training subjects). Normality of data will be tested using the  
Kolmogorov-Smirnov test. Depending on whether normality 
assumption hold, a two group t-test or Wilcoxon rank-sum test will 
be used to compare between the two treatment groups. A P-value 
of less than 0.05 is considered statistically significant unless 
otherwise specified.  
The secondary endpoints will be evaluated using the Holm-
Bonferroni method to ensure the overall type I error rate is 
controlled at the 0.05 level. 
Cardiovascular Variables will be summarized for both groups. The 
incidence of hypotension will be summarized and compared to 
anesthesia sedation levels. 
The anesthetic requirements with the BIS™ value, the percentage of 
time during maintenance with BIS™ values within the specified ranges, 
and number of episodes and duration of burst suppression will be 
assessed for both treatment groups.  
Additional endpoints, including PAED scale, Pain Rating Score and a 
subgroup analysis for subjects requiring neuromuscular blockade, will 
be summarized using descriptive statistics for each group and groups 
combined. 

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4. Introduction  
4.1. Background  
4.1.1. 
Basics of Anesthesia & Anesthetics 
General anesthesia (GA) is a reversible state of controlled unconsciousness that is achieved with drugs 
that prevent awareness, pain, recall, distress, and movement in patients during surgery. Two critical 
components of general anesthesia are hypnosis and analgesia. Maintaining an adequate level of 
anesthesia depth is essential to the attenuation of these responses. The analgesic component may be 
considered as the probability of tolerance to a painful stimulus. Tolerance means the absence of a 
response being either a somatic response (e.g., movement, sweating, eye-opening) or a hemodynamic 
response (increase in heart rate or blood pressure). When the state of general anesthesia is inadequate 
for the level of nociceptive stimulation from surgery, the heart rate and blood pressure can increase 
dramatically, alerting the anesthesiology provider to the possibility of increased nociception and arousal. 
Higher doses of an anesthetic are necessary to prevent reactions to more intense surgical stimuli. This fact 
has suggested that different states of anesthesia fall along a continuum of depth, with deeper anesthesia 
eliminating reactions to stronger stimuli [2]. Thus, the anesthesiologist needs to know when a patient has 
reached a depth of anesthesia commensurate with an impending stimulus. The patient expects a surgical 
procedure to be safe and painless, with the assurance that throughout the procedure, s/he is asleep, 
without any perception or memory of what happened during that period.  
4.1.2. 
EEG Monitoring in Anesthesia 
Since 1939, anesthesiologists have known about changes in the electroencephalogram (EEG) that are 
produced by anesthetic agents [3]. Many of the changes that occur in the brain with changes in anesthetic 
states can be readily observed in unprocessed EEG recordings. Different behavioral and 
neurophysiological states induced by anesthetics are associated with varying EEG waveforms. The earliest 
use of the EEG in anesthesia tested the effects of barbiturates, eventually leading to the recognition of 
particular sequential effects shown in Figure 1 [4, 5]. The first changes induced by barbiturates in the EEG 
are 20-30 Hz (initial rapid response) waves, followed by the superimposition of 5-12 Hz alpha waves. Loss 
of consciousness occurs just as the initial rapid response yields to the slower oscillations. Spindle bursts 
of 5-12 Hz become prominent, and in turn, decline as the EEG develops large polymorphic waves of 1-3 
Hz. When this slow polymorphic activity becomes dominant, the patient tolerates skin incision. At still 
higher concentrations of barbiturates, the EEG displays periods of suppression, each terminating with 
“burst” of renewed activity, which contains high-frequency components. The burst gradually subsides as 
it leads into the next episode of suppression. This combination of alternating phases of high-amplitude 
and low-amplitude periods is called “burst suppression.”  
Monitoring the depth of anesthesia could help the anesthesia professional avoid intraoperative 
awareness and ensure that an appropriate dose of anesthetic drugs is given for each patient. The lightness 

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of anesthesia can result in awareness with a recall of events that happen in the operating room. 
Anesthesia that is too deep could cause hemodynamic disturbances necessitating the use of 
vasoconstrictor agents, which constrict blood vessels to maintain normal blood pressure and cardiac 
output. Overly deep anesthesia can also result in respiratory depression requiring respiratory assistance 
postoperatively [3]. There is no objective scale that measures “too light” or “too deep” anesthesia. 
Bispectral Index (BIS™) technology monitoring uses processed EEG signals to measure sedation depth 
based on level of consciousness (LOC) signals. It allows anesthesia providers to titrate general anesthesia 
to achieve the desired LOC on the brain [3, 6]. BIS™ technology consists of a sensor, a digital signal 
converter, and a monitor. The sensor is placed on the patient’s forehead to pick up the electrical signals 
from the cerebral cortex and transfer them to the digital signal converter. BIS™ values quantify changes 
in the electrophysiologic state of the brain during anesthesia. Overall, a BIS™ value below 60 is associated 
with a low probability of response to commands. The BIS™ is a continuously processed EEG parameter 
that correlates to the patient’s level of hypnosis, where 100 = awake and 0 = flat-line EEG. The BIS™ 
parameter was designed to correlate with “hypnotic” clinical endpoints (sedation, lack of awareness, and 
memory) and to track changes in the effects of anesthetics on the brain. Figure 1 reflects a general 
association between clinical state and BIS™ values. Ranges are based on results from a multi-center study 
[6] of the BIS™ system involving the administration of specific anesthetic agents. BIS™ values and ranges 
assume that the EEG is free of artifacts that can affect its performance. Titration of anesthetics to the BIS™ 
range should be dependent upon the individual goals established for each patient. These goals and 
associated BIS ranges may vary over time and in the context of patient status and treatment plan.  
 
Figure 1: BIS™ Range Guidelines; a general association between clinical state and BIS™ values 
4.1.3. 
BIS Monitoring in Pediatric Populations 
Several studies demonstrate that BIS™ monitoring in children and infants provides a similar response to 
those achieved in the adult population [7-9]. Few selected published or sponsor supported studies have 

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demonstrated that using the Bispectral Index (BIS™) system correlates significantly with the level of 
responsiveness and the depth of anesthesia in pediatric patients. 
4.1.3.1. 
Published Studies 
A prospective study to investigate sedation with dual monitoring of Comfort Score (CS) and BIS™ module 
using BIS™ four-electrode or BIS™ pediatric sensors in open muscle biopsies in 30 children ages 1-18 was 
conducted by Tschiedel and colleagues [10]. The purpose of this study was to correlate and compare BIS™ 
and CS. None of the participants in the study experienced side effects related to the anesthesia or 
procedure. In 25 patients, sedatives were reduced according to low BIS™ values (<60). No unintended 
anesthesia awareness was noted during the study period. This study supported that Bispectral Index 
provides an additional helpful tool to guide sedation/analgesia in minor surgical procedures in children. 
BIS™ values </=60 correlated with sufficient depth of sedation and prevented unintended awareness. 
Additionally, BIS measurement allowed for distinct regulation of depth of sedation without prolonged 
sedation/analgesia due to unintended overdose. 
A randomized, controlled trial aimed to determine if the depth of sevoflurane anesthesia impacts 
emergence agitation (EA) in children undergoing ophthalmic surgery was conducted [11]. Children, ages 
2 to 8, were randomized into light sedation (BIS™ 55-60) or deep sedation (BIS™ 40-45) groups. EA was 
measured using the Pediatric Assessment of Emergence Delirium (PAED) scale. Peak PAED scores (light: 
7.7 ± 4.6; deep: 8.6 ± 5.3, p= 0.45) and EA incidence (light: 1; deep: 2) were similar between groups.  While 
there was a significant mean BIS™ score difference between groups, the relationship between BIS™ score 
and end-tidal sevoflurane concentration was weak (r= -.03). 
The effects of Bispectral index monitoring on hemodynamics and recovery profile in developmentally 
delayed pediatric patients undergoing dental surgery were investigated in 40 patients by Fredrick and 
colleagues [11]. Participants were randomized into MAC-guided sevoflurane anesthesia (Group 1) or BIS™ 
guided anesthesia (Group 2). The impact of BIS™ monitoring on the recovery time of developmentally 
delayed children undergoing dental surgery was evaluated. The general anesthesia was maintained with 
1-2 minimum alveolar concentration (MAC) of sevoflurane in oxygen by standard practice. The recovery 
profile, time to spontaneous ventilation, extubation, ability to open eyes, and PACU discharge were 
evaluated. The BIS™ guided group had improved recovery times. There were significant differences 
between recovery times and Non-communicating Children's Pain Checklist - Postoperative Version 
(NCCPC-PV) scores of two groups. Time to spontaneous ventilation [Difference in means (95% CI); 3.17 
(1.79-4.54) P < 0.001], extubation [Difference in means (95% CI); 3.13 (1.66-4.60) P < 0.001], open eyes 
[Difference in means (95% CI); 3.97 (2.34-5.59) P < 0.001], and PACU stay time [Difference in means (95% 
CI); 23.55 (18.08-29.01) P < 0.001] were significantly shorter in Group 2. In conclusion, results suggest that 
routine BIS™ monitoring may be beneficial due to its favorable effects on the recovery profile in 
developmentally delayed pediatric patients. 

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Degoute and colleagues [8] conducted a prospective study to evaluate the correlation between BIS™ and 
the clinically assessed hypnotic component of anesthesia (CA score) in 27 pediatric and 27 adult patients 
when sevoflurane as the sole anesthetic was used. BIS™ and CA were compared at the loss of 
consciousness (LOC) and the recovery of consciousness (ROC), Figure 2. Mean (SD) BIS™ decreased 
significantly at LOC in children and adults from 94 (2.7) to 87.4 (4) and from 96.2 (2) to 86.7 (4.4), 
respectively, without any difference between groups. Correlation coefficients (p) between BIS™ and CA 
at LOC were -0.761 in children and -0.911 in adults. BIS™ index increased significantly at ROC in children 
and adults from 74.1 (4.2) to 86.7 (2) and from 80.2 (5) to 90.7 (3), respectively. Correlation coefficients 
between BIS™ and CA in ROC were -0.876 in children and -0.837 in adults.  
 
Figure 2: EEG BIS™ in child and adult patients (27 in each group). Abbreviations: Awake=baseline values, LOC - loss of 
consciousness; LOM - loss of movement; SI - skin incision; SV - spontaneous ventilation; ROC - recovery of consciousness. Data 
are post stimulus. Results are mean ± SD. ***Significantly different from baseline values within a group (P<0.001); one-way 
analysis of variance with Bonferroni's correction where indicated. 
In conclusion, the study suggested that the BIS™ values at ROC were not different from those at LOC in 
either group. It was found that the correlation between the BIS™ index and end-tidal sevoflurane 
concentration in children to be similar to that observed in adults. 
4.1.3.2. 
 Sponsor Supported Studies 
 
The Effect of Bispectral Index Monitoring on Anesthetic Use and Recovery in Children Anesthetized 
with Sevoflurane in Nitrous Oxide 
A prospective, randomized, observer-blinded study was designed to evaluate the effect of BIS™ 
monitoring on anesthetic use and recovery characteristics in pediatric patients [12]. Two hundred forty 
(240) patients were enrolled in the study. During a baseline phase before starting randomization, data of 

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38 patients were collected “historical controls.” These control patients were anesthetized according to 
standard institutional practice.  
Two hundred two (202) patients age 0–18 years were randomized into one of two groups: standard 
practice (SP) and BIS™ guided (BIS™). Patients age 0–3 years, undergoing inguinal hernia repair (IH), and 
patients age 3–18 years, undergoing tonsillectomy and/or adenoidectomy (TA), were selected, Table 1. 
All patients were anesthetized with sevoflurane in 60% N2O/O2.  
In the BIS™ group, anesthetic delivery was adjusted to achieve a target BIS™ values of 45–60 during 
maintenance and 60–70 during the last 15 minutes of the procedure.  
Table 1: Demographic Data (mean ± SD) 
Control 
SP 
BIS 
Infants (age 0–6 mo), hernia repair  
Number 
8 
28 
32 
Sex (M/F) 
5/3 
23/5 
27/5 
Age (yr) 
0.2 ± 0.1 
0.2 ± 0.1 
0.2 ± 0.1 
Weight (kg) 
4.8 ± 1.0  
5.1 ± 1.6 
5.5 ± 1.6 
Duration of Surgery (min) 
26.2 ± 7.4 
32.0 ± 17.6 
30.1 ± 14.5 
Infants and small children (6 mo–3 yr), hernia repair 
Number 
11 
34 
33 
Sex (M/F) 
7/4 
29/5 
28/5 
Age (yr) 
1.8 ± 1.1 
1.9 ± 1.0 
2.2 ± 1.0 
Weight (kg) 
11.5 ± 3.6 
11.9 ± 2.8 
13.3 ± 3.0 
Duration of Surgery (min) 
20.8 ± 12.0 
25.7 ± 11.8 
24.8 ± 14.9 
Children (age 3–18 yr), tonsillectomy and/or adenoidectomy 
Number 
19 
35 
40 
Sex (M/F) 
10/9 
23/12 
26/14 
Age (yr) 
5.9 ± 2.0 
6.1 ± 2.6 
6.7 ± 2.5 
Weight (kg) 
24.8 ± 9.5 
27.7 ± 14.7 
26.9 ± 10.6 
Duration of Surgery (min) 
28.1 ± 14.2  
33.2 ± 20.3 
27.7 ± 17.1 
SP = Standard Practice group; BIS = Bispectral Index group 
 
In the patients 0–6 months of age undergoing IH, sevoflurane concentrations during maintenance (2.0 ± 
0.4% SP, 0.9 ± 0.8 BIS™), during the last 15 minutes (1.6 ± 0.4% SP, 0.6 ± 0.6% BIS™), and at the end of the 
procedure (1.1 ± 0.6% SP, 0.3 ± 0.3% BIS™) were smaller in the BIS™ group, Table . Emergence and 
recovery measures, Table , were unaffected by BIS™ titration. In the children 6 months to 3 years of age, 
there were no significant differences between the SP and BIS™ groups in anesthetic use or recovery 
measures. 

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Table 2: Intraoperative Data for Control, Standard Practice (SP), and BIS Groups (mean ± SD) 
Control 
SP 
BIS 
Infants (age 0–6 mo), hernia repair 
  
  
  
Average ET sevoflurane, maintenance (%) 
2.2 ± 0.7 
2.0 ± 0.4 
0.9 ± 0.8* 
Average ET sevoflurane, last 15 min (%) 
2.0 ± 0.9 
1.6 ± 0.4 
0.6 ± 0.6* 
Average ET sevoflurane, end of procedure (%) 
1.5 ± 0.9 
1.1 ± 0.6 
0.3 ± 0.3* 
BIS™ maintenance 
34.9 ± 5.8 
36.2 ± 11.8 
35.7 ± 9.6 
BIS™ last 15 min 
34.9 ± 7.0 
40.4 ± 12.5 
41.0 ± 10.5 
BIS™ end of procedure 
37.7 ± 7.1 
43.1 ± 17.5 
48.3 ± 12.9 
Infants and small children (6 mo–3 yr), hernia repair 
  
  
Average ET sevoflurane, maintenance (%) 
1.8 ± 0.4 
2.3 ± 0.6 
2.2 ± 0.5 
Average ET sevoflurane, last 15 min (%) 
2.0 ± 0.7 
2.0 ± 0.6 
1.9 ± 0.5 
Average ET sevoflurane, end of procedure (%) 
1.5 ± 0.9 
1.4 ± 0.8 
1.2 ± 0.6 
BIS™ maintenance 
55.8 ± 15.2 
50.0 ± 14.1 
54.8 ± 9.1 
BIS™ last 15 min 
51.8 ± 14.4 
54.5 ± 14.7 
55.9 ± 10.4 
BIS™ end of procedure 
56.2 ± 18.4 
61.4 ± 15.3 
64.5 ± 10.1 
Children (age 3–18 yr), tonsillectomy and/or adenoidectomy 
  
  
Average ET sevoflurane, maintenance (%) 
2.4 ± 0.4 
2.4 ± 0.6 
1.8 ± 0.4* 
Average ET sevoflurane, last 15 min (%) 
2.2 ± 0.5 
2.1 ± 0.7 
1.6 ± 0.6* 
Average ET sevoflurane, end of procedure (%) 
1.6 ± 0.7 
1.5 ± 0.7 
1.1 ± 0.6 
BIS™ maintenance 
37.2 ± 7.5 
39.6 ± 11.5 
47.2 ± 10.1 
BIS™ last 15 min 
43.6 ± 11.2 
44.8 ± 11.3 
55.7 ± 7.9* 
BIS™ end of procedure 
50.1 ± 15.3 
53.0 ± 16.0 
63.0 ± 8.6* 
ET = end-Tidal; SP = Standard Practice group; BIS = Bispectral Index group 
* P < 0.05 versus SP group. 
 
Table 3: Time from End of Procedure Needed to Achieve the Primary Recovery End Points for the Control, SP, and BIS groups 
(mean ± D) 
Control 
SP 
BIS 
Infants (age 0–6 mo), hernia repair 
First response (min) 
3.3 ± 1.8 
4.3 ± 4.0 
2.9 ± 2.6 
Extubation (min) 
10.9 ± 7.5 
9.3 ± 8.9 
5.0 ± 2.6 
Ready to discharge (min) 
29.0 ± 11.1 
25.8 ± 19.7 
18.3 ± 8.2 
Infants and small children (6 mo–3 yr), hernia repair 
First response (min) 
3.4 ± 1.9 
4.1 ± 2.4 
3.8 ± 2.5 
Extubation (min) 
4.2 ± 3.0 
7.6 ± 4.1 
6.5 ± 3.1 
Ready to discharge (min) 
21.1 ± 8.0 
21.1 ± 9.7 
20.3 ± 8.8 
Children (age 3–18 yr), tonsillectomy and/or adenoidectomy 
First response (min) 
6.7 ± 3.7 
7.0 ± 3.9 
4.2 ± 3.7* 
Extubation (min) 
11.3 ± 5.0 
11.3 ± 5.9 
7.1 ± 3.7* 

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Ready to discharge (min) 
22.0 ± 9.2 
26.7 ± 11.2 
20.0 ± 7.9* 
SP = Standard Practice group; BIS = Bispectral Index group 
* P < 0.05 versus SP group. 
In conclusion, in the TA age 3–18 year group, BIS™ monitoring was associated with a significant reduction 
in end-tidal sevoflurane concentration during maintenance (2.4 ± 0.6%, SP and 1.8 ± 0.4% BIS™, mean ± 
SD) and during the last 15 min of the procedure (2.1 ± 0.7, SP and 1.6 ± 0.6, BIS), refer to Table . Recovery 
times were 25%–40% faster in BIS-titrated patients, Table . 
Pediatric Evaluation of the Bispectral Index (BIS™) Monitor and Correlation of BIS™ with End-tidal 
Sevoflurane Concentration in Infants and Children 
Denman and colleagues conducted a prospective clinical study in children undergoing general anesthesia. 
Seventy-seven (77) pediatric patients were studied under the two protocols [9]. An initial group of 55 
patients, observational protocol, had BIS recorded during routine general anesthetics. The anesthetist was 
not aware of the BIS™ value. Sedative-hypnotic drugs used included methohexital, propofol, sevoflurane, 
isoflurane, desflurane, nitrous oxide, and diazepam. For this group, BIS™ values were analyzed for three 
prospectively defined case milestones: before the induction of anesthesia, during maintenance, and at 
emergence from anesthesia. In addition, a “nadir BIS™,” the lowest BIS™ value occurring within the 10-
min period after the induction of anesthesia, was recorded. In addition, data from 26 adults collected 
previously at the same clinical endpoints were used to compare BIS, Table 4 and Figure 3.   
Table 4: BIS™ (Bispectral Index) Values at Case Milestones in Un-premedicated Children and Infants Versus Adults 
 
Awake 
Nadir 
Maintenance 
Emergence 
Pediatric 
 
 
 
 
n 
26 
49 
44 
32 
Mean BIS™ 
94.12 
16.36 
42.39 
83.51 
SD 
4.53 
12.73 
14.18 
11.63 
Adult 
 
 
 
 
n 
57 
20 
20 
58 
Mean BIS™ 
96.60 
36.30 
44.90 
80.19 
SD 
3.31 
9.08 
10.76 
12.33 
Ρ 
NS 
0.00001 
NS 
NS 
Powera 
 
0.99 
0.99 
0.96 
0.91 
a Power to detect a difference of 10 or more BIS units between adults and children with α = 0.05 
 
 

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Figure 3:  Bispectral index (BIS™) values at case milestones 
in adults, infants, and children. The nadir BIS™ for the 
combined pediatric groups was significantly lower than 
that for adults. Error bars represent sd. 
Figure 4: Bispectral index (BIS™) values versus end-tidal 
sevoflurane concentration. The difference between infants 
and children was statistically significant. The solid circles 
represent the children and the open circles represent the 
infants. 
 
 
Twenty-two patients (11 infants and 11 children) were studied while receiving sevoflurane as the primary 
anesthetic, and BIS™ measurements were recorded at five steady-state end-tidal sevoflurane 
concentrations of 3.0%, 2.0%, 1.5%, 1.0%, and 0.5%.  Mean BIS and standard deviation were determined 
at each concentration of sevoflurane, Figure 4.  
 
BIS™ responses during general anesthesia were observed in infants and children and compared with 
values measured in adults. No difference between unpremeditated children and adults is seen in BIS™ 
values before the induction, during maintenance, or at emergence. BIS™ nadir is lower in children than 
adults, and this difference is statistically significant. The study demonstrated that BIS™ values in awake 
and anesthetized children and infants were comparable to values in adults. 
The use of BIS™ during general anesthesia improves the titration of anesthetics in adults. The data from 
both of these pediatric studies suggest that the same methods may be applied to pediatric patients. 
4.2. Purpose 
The purpose of this study is to investigate the relationship between BIS™ and anesthetic agents in 
pediatric patients ages 4-18.  

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5. Objectives and/or Endpoints 
5.1. Objectives 
5.1.1. 
Primary Objective(s) 
The primary objective of this study is to characterize BIS™ performance with the anesthetic agent in 
pediatric patient ages 4 to 18 years. 
5.2. Endpoints 
5.2.1. 
Primary Endpoint(s) 
The end‑tidal sevoflurane concentration in both patient groups acquired during maintenance of 
anesthesia. The study will be considered a success if the primary objective, achieving statistical and 
clinical significance in obtaining the end-tidal sevoflurane concentration during maintenance in both 
patient groups, is achieved. 
5.2.2. 
Secondary Endpoint(s) 
Secondary endpoint(s):  
• 
Recovery assessments in patients receiving monitoring compared to standard anesthetic practice 
(instructions for collection contained in Study Procedures and Assessments): 
• 
Emergence,  
• 
Emergence is defined as the time when any of the following first occurred: 
• 
Eyes open spontaneously 
• 
Crying or phonating 
• 
Purposeful movements 
• 
PACU discharge readiness using Modified Aldrete Score 
• 
Anesthesia Airway Management (AAM) will be noted: 
o 
Awake and Deep Extubation (endotracheal tube (EET) vs. laryngeal mask airway (LMA) 
o 
Airway reflexes (e.g., coughing, choking, laryngospasm) 
Additional/Exploratory Endpoints: 
• 
Clinical Anesthesia Assessment, recorded as the incidence of movements, grimacing, eye opening, tearing, 
sweating, mydriasis and cardiovascular changes while undergoing anesthesia 
• 
Pediatric Anesthesia Emergence Delirium (PAED) 
• 
Wong-Baker FACES Pain Rating Score 

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6. Study Design  
This is a multi-center, prospective, randomized controlled study to collect data to compare the 
performance of standard practice (SP) group with the BIS™ monitoring (BIS™) group. Pediatric patients 
between the ages of 4 to 18 years undergoing routine sevoflurane general anesthesia with an expected 
surgical procedure duration of 30 minutes or more will be recruited. General surgeries include abdominal, 
urological, orthopedic, ophthalmological, or other procedures approved by the Medtronic study team 
with an American Society of Anesthesiologists physical status of I - III. Children will be recruited from the 
preoperative clinic and will be divided into three age groups:   
A training group, comprising of the first 2 - 4 subjects at each site will be enrolled to train the site team 
on the new technology and to determine the quality of data collection before randomization. Afterward, 
randomization will proceed based on the Sponsor’s assessment of data quality.  
6.1. Duration 
The planned duration of the study is 8 - 12 months. The consented study subject duration of 
participation is not to exceed the duration of the surgery and post-surgical discharge.  
6.2. Rationale  
Pediatric patients present a unique challenge during anesthetic delivery and monitoring of sedation. 
Although a number of studies have been conducted to assess the reliability of BIS™ technology in 
pediatrics, validation presents more of a challenge in children as compared to adults. The EEG in young 
children is more age-dependent, with brain maturation and synapse formation continuing until about the 
age of four [15]. Further, with young children, assessing sedation or sleep with simple responses to voice 
commands is unreliable, and many clinical endpoints can be ambiguous in this population. In younger 
children, it is also challenging to distinguish purposeful movements from nonspecific responses. Also, 
healthy volunteer studies relating to anesthetic concentration to the clinical endpoints performed in 
adults cannot be replicated in the pediatric population. This clinical study is designed to capture the 
performance of BIS with anesthetic agents in the pediatric patient population.  
The BIS™ ranges are selected based on the prospective, randomized, observer-blinded study listed in 
Section 4.1.3.2. Sebel and his and colleagues enrolled 240 patients from which 38, control group, subject’s 
data were used to define BIS™ targeted ranges. These control patients were anesthetized according to 
standard institutional practice; the BIS™ values were concealed for this group. For the BIS™ group, 
• 
4 to 8 years 
• 
9 to 12 years  
• 
13 to 18 years 

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anesthetic delivery was adjusted to achieve a target BIS™ values of 45 – 60 during maintenance and 60 –
75 during the last 15 minutes of the surgical procedure. The results of this study supported that BIS™ 
guided anesthetic management was associated with a significant reduction in anesthetic consumption 
and faster recovery. Based on the published results, and to support this study, the guided anesthetic 
administration will be achieved using a BIS™ target range of 45 – 60 during maintenance of anesthesia 
and 60 –75 beginning of skin closure. 
The de-identified data collected in this study also may be used for future product development.  
7. Product Description 
7.1. General 
The BIS™ complete monitoring system is a user-configurable patient monitoring system designed to 
monitor the hypnotic state of the brain based on the acquisition and processing of EEG signals. The BIS™ 
complete system processes raw EEG signals to produce a single number, called the BIS™ index, which 
correlates with the patient's level of hypnosis. A sensor placed on the patient’s head transmits EEG signals 
to the BISx™ unit. The BISx™ unit filters and digitizes the signal, analyzes it for the artifact, and processes 
it using digital signal processing techniques to derive processed EEG parameters to a single Bispectral 
Index (BIS™), and finally sends the processed data to the monitor for display. The purpose of processing 
the EEG waveform data is to extract characteristic features from the complex signal that the BIS™ 
algorithm can utilize to derive BIS Index. 
Table 3: System product/ component information for the US 
Model Number  
Component (Manufacturer) 
Investigational or Market-released 
185-0151 
BIS™ Complete Monitor (Medtronic) 
Market-released 
185-1014-AMS 
BISx™ (Medtronic) 
Market-released 
186-0107 
Patient Interface Cable (Medtronic) 
Market-released 
N/A 
BIS™ Sensor (Medtronic) 
Market-released 
N/A 
Detachable Power Cord (Medtronic) 
Market-released 
7.2. Manufacturer 
BIS™ Complete Monitoring System, BISx™, Patient Interface Cable, BIS™ Sensor, Detachable Power Cord 
by (15 Hampshire St, Mansfield MA) Medtronic Inc. 

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7.3. Packaging 
The sponsor is responsible for the packaging and labeling of the device for shipment to the study site. 
Research conducted for this study will utilize devices cleared through the 510(k) regulatory process. FDA 
cleared devices are being used within the FDA-cleared indications for use (IFU) and do not require special 
labeling.  
7.4. Intended Population 
The study will be focusing on the pediatric patient population, ages 4 to 18, refer to Section 9.4.  
7.4.1. 
BIS™ Complete Monitoring System Indications for Use 
The BIS™ EEG complete monitoring system is intended for use under the direct supervision of a licensed 
healthcare practitioner or by personnel trained in its proper use. The system and its associated parameters 
are intended for use on adult and pediatric patients within a hospital or medical facility, providing patient 
care to monitor the state of the brain by data acquisition of EEG signals. The BIS™ index, one of the 
Complete Monitor output parameters, may be used as an aid in monitoring the effects of Desflurane, 
Isoflurane, Propofol, and Sevoflurane with balanced anesthetic techniques in Adults, and with Sevoflurane 
in Pediatrics. BIS™ usage with Propofol in adults may be associated with a reduction in primary anesthetic 
use and a reduction in emergency and recovery time. Use of the BIS™ index for monitoring to help guide 
anesthetic administration may be associated with the reduction of incidence of awareness with recall in 
adults during general anesthesia and sedation.  
7.4.2. 
Pulse Oximetry System Indications for Use 
The Nellcor™ N-600x Pulse Oximetry System and Nellcor™ Sensors with OXIMAX technology are indicated 
for prescription use only for the continuous non-invasive monitoring of functional oxygen saturation of 
arterial hemoglobin (SpO2) and pulse rate. The N-600x Pulse Oximeter is intended for use with neonatal, 
pediatric, and adult patients during both no motion and motion conditions and for patients who are either 
well or poorly perfused, in hospitals, hospital-type facilities, intra-hospital transport, and home 
environments. 
7.5. Equipment 
7.5.1. 
BIS™ Complete Monitoring System  
The BIS™ Complete Monitor is an easy to use microprocessor-based EEG monitor. The BIS™ Complete 
Monitor reports a BIS™ value by acquiring up to two channels of EEG from sensors attached to the 
patient’s head and performing the computations necessary to produce the BIS™ index. The BIS™ index is 

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then numerically displayed for the clinician’s use. The BIS™ Complete Monitoring System consists of the 
following components (Figure 5). BIS™ Complete Monitor 
Figure 5: The BIS™ Complete Monitoring System. 1 - BIS™ Monitor 2 - Monitor Interface Cable; 3 - BIS™ Pediatric Sensor; 4 - 
Patient Interface Cable (PIC); 5 - BISx™ (LoC 2Channel); 6 - BIS™ QUATRO Sensor  
7.5.1.1. 
BIS™ Complete Monitor 
BISx™ Modules 
The BISx™ receives, filters, digitizes and processes patient EEG signals. It is located close to the patient's 
head, where the EEG signal is less subject to interference from other medical equipment. The BISx™ is 
shown in Figure 6. Its long flexible Monitor Interface Cable connects to the front of the monitor. The 
Patient Interface Cable (PIC) connects the BIS™ sensor to the BISx™. The attachment clip on the BISx™ is 
used to secure it in a convenient location near the patient's head. The BISx™ are mutually exclusive parts 
of the BIS™ Complete Monitoring System. The BISx™ Module processes up to two channels of EEG and 
computes the BIS™ value and other EEG parameters.  
 
• 
BIS™ Complete Monitor 
• 
BISx™ (BISx™ will be used in this study) 
• 
Patient Interface Cable (PIC)  
• 
BIS™ Sensors 
• 
Monitor Interface Cable 

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Figure 6: BISx™ Module: 1-Monitor Interface Cable; 2-Patient Interface Cable; and BISx™ (LoC 2Channel) 
Patient Interface Cable 
Covidien BIS™ Sensor Patient Interface Cable (PIC) connects the BISx4™ to the BIS Sensor, refer to Figure 
6. 
BIS™ Sensor  
The sensor is the single-use component of the BIS™ Monitoring System and should be replaced after each 
use.  
BIS™ Sensors 
BIS™ Pediatric and QUATRO Sensors, Figure 7, are designed with a 4 electrode pre-gelled EEG electrode 
array that is applied directly to the patient’s forehead to transmit EEG signals to the BISx™ Module. The 
sensor will be applied per IFU. 
BIS™ Pediatric Sensor 
BIS™ Pediatric Sensor is designed with a 4 electrode pre-gelled EEG electrode array that is applied directly to 
the patient’s forehead to transmit EEG signals to the BISx™ Modules, Figure 7. The sensor will be applied per 
IFU. 
 
 
 
BIS™ QUATRO Sensor 
BIS™ Pediatric Sensor 

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            Figure 7: BIS™ Sensors 
Nellcor™ N-600x Pulse Oximetry System  
The FDA-cleared Nellcor™ N-600x Pulse Oximetry System with N-600X Pulse Oximeter and age-
appropriate Nellcor™ Sensors and Cables with OXIMAX technology (Figure 8) or another monitor may be 
provided by the sponsor to the study site. The laptop may be provided to stream SpO2 data. 
 
Figure 8: Nellcor™ OxiMax N-600x Pulse Oximeter 
Nellcor™ SpO2 Adhesive Sensor 
N-600x pulse oximeter paired with the following type of sensors based on the subject’s weight ranges 
(Figure 9): 
• 
For subjects weighing between 3 and 20 kg: MAXI sensor 
• 
For subjects weighing less than 3 kg or weighing more than 40 kg: MAXN sensor (or other production 
sensors such as Nellcor™ OxySoft sensor) 
• 
For subjects weighing between 10 and 50 kg: MAXP sensor 
• 
For subjects weighing more than 30 kg: MAXA sensor 

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The Nellcor™ Infant SpO2 Sensor, model MAXI, is 
indicated for single patient use when continuous 
noninvasive arterial oxygen saturation and pulse rate 
monitoring are required for patients weighing between 3 
and 20 kg. 
 
 
 
The Nellcor™ Neonatal-Adult SpO2 Sensor, model MAXN, is 
indicated for single patient use when continuous noninvasive 
arterial oxygen saturation and pulse rate monitoring are 
required for neonates weighing less than 3 kg or adults weighing 
more than 40 kg. 
 
The Nellcor™ Pediatric SpO2 Sensor, model MAXP, is 
indicated for single patient use when continuous non-
invasive arterial oxygen saturation and pulse rate 
monitoring are required for patients weighing between 
10 and 50 kg. 
The Nellcor™ Adult SpO2 Sensor, model MAXA(L) is indicated for 
single patient use when continuous non-invasive arterial oxygen 
saturation and pulse rate monitoring are required for patients 
weighing more than 30 kg. 
Figure 9: SpO2 Sensors  
7.6. Product Use 
A member of the Medtronic team may set up the BIS™ system and Pulse Oximeter at each participating 
research site in person or via remote webcam to ensure all equipment is fully functional as needed. 
Specific instructions to the Site Investigator and staff on system set up and use, sensor application, and 
data transfer will be provided before subject enrollment. 

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7.7. Product Training Requirements 
Prior to site activation or subsequent involvement in clinical study activities, Medtronic will provide clinical 
study training relevant and pertinent to the involvement of personnel conducting clinical study activities 
and investigator responsibilities. Principal Investigators (PI) participating in the clinical study and the 
associated clinical study staff will receive training on the device and system (including but not limited to 
device characteristics, storage requirements, warnings, precautions, and contraindications.) It is the 
responsibility of the PI at each participating site to assure any staff performing tasks related to the clinical 
trial (e.g., Study Coordinators, Study Nurses, Sub-Investigators, etc.) have been appropriately trained, 
training documented and included on the Delegated Task List. 
7.8. Product Receipt and Tracking 
The PI or designee will maintain records of devices/products or products provided by Medtronic free of 
charge delivery to the study site, e.g., device shipping forms, return forms, eCRFs, source worksheets. The 
following records will be maintained at a minimum for product delivery, receipt, and tracking at the site: 
dates, quantities received, lot/serial numbers, disposition of device, and expiration dates, as applicable.  
7.9. Product Storage 
Devices or products provided by Medtronic free of charge must be stored in a secured area. The method 
of storage shall prevent the use of devices/products for other applications than mentioned in this Clinical 
Investigation Plan. In addition, all information for the use, storage, and handling of the device/product, as 
indicated in the IFU and User Manual, must be taken into account. 
7.10. Product Return 
All monitors provided by Medtronic free of charge should be returned to Medtronic and documentation 
of return, e.g., device return forms should be maintained. Devices that are single use provided by 
Medtronic and used in the study should be discarded and documented as discarded on the device 
accountability log unless non-functioning. Non-functioning investigational devices must be returned to 
Medtronic as soon as possible for investigation. Instructions for returning the device will be provided. Un-
used devices will be returned to Medtronic at the end of the study.  
7.11. Product Accountability  
Devices/products will be traced during the clinical study by specific serial numbers (or lot numbers) 
assigned to each device/product. The Investigator is responsible for the maintenance of a Product 
Accountability as tracked on source worksheets, device shipment/return forms, and device eCRFs. On this 

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documentation, the receipt, use, return, and disposal of the investigational devices/products shall be 
documented. At the end of the clinical study, the Principal Investigator or delegate must sign and date the 
applicable eCRFs.  
8. Study Site Requirements 
8.1 
Investigator / Investigation Study Site Selection 
All investigators managing the subject’s anesthesia must be qualified practitioners and experienced in the 
diagnosis and treatment of subjects undergoing anesthesia.  All physicians must be trained in the handling 
of the BIS™ Complete Monitoring System. 
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the subjects involved 
in the clinical investigation. 
The principal investigator shall: 
• 
Be qualified by education, training, and experience to assume responsibility for the proper 
conduct of the clinical investigation 
• 
Be experienced in the field of application and training in the use of the BIS™ Complete 
Monitoring System 
• 
Disclose potential conflicts of interest, including financial, that interfere with the conduct of 
the clinical investigation or interpretation of results 
• 
Be able to demonstrate that the proposed investigational study site: 
 
Has the required number of eligible subjects needed within the recruitment period 
 
Has one or more qualified investigators, a qualified investigational study site team and 
adequate facilities for the foreseen duration of the clinical investigation 
 
Study site personnel training will be completed and documented prior to participation in this study. 
8.2 
Study Site Activation 
During the activation process (prior to subject enrollment), Medtronic will train study site personnel on 
the clinical investigation plan, on relevant standards and regulations, informed consent, and on data 
collection and reporting tools. If new members join the study site team, they will receive training on the 
applicable study requirements relevant to their role before contributing to the study. 
Prior to performing study related activities, all regulatory requirements shall be fulfilled, including, but 
not limited to the following:  
• 
IRB approval (and voting list, as required by local law) of the current version of the CIP and IC.  

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• 
RA approval or notification (as required per local law)  
• 
Fully executed CTA  
• 
Financial disclosure  
• 
CV of investigators and key members of the investigation study site team.    
• 
Documentation of delegated tasks 
• 
Documentation of study training.  
• 
Additional requirements imposed by local regulations, the IRB and RA shall be followed, if 
appropriate.  
 
In addition, all participating study site staff must be trained on the current version of the CIP as well as on 
the applicable study requirements depending on their role and must be delegated by the principal 
investigator to perform study related activities.   
 
Medtronic will provide each study site with documentation of study site/investigator readiness; this letter 
must be received prior to performing study related activities.  
8.3 
Role of the Sponsor Representatives 
In addition to performing monitoring and auditing activities, sponsor representatives may provide 
support at the study site as required for the study under supervision of the Principal Investigator, 
including: 
• 
Provide study training relevant and pertinent to the involvement of personnel conducting 
study activities and investigator responsibilities 
• 
Technical support at SIV and training cases under the supervision of a study investigator, but 
no data entry, shall be performed by Medtronic personnel or their representatives at study 
sites 
9. Selection of Subjects 
9.1. Study Population 
Male and female pediatric subjects between the ages of 4 to 18 years undergoing routine sevoflurane 
general anesthesia will be enrolled. The first 2 - 4 subjects per each site will be used for training and to 
check the data quality. After training subjects have been enrolled, randomization will proceed based on 
the Sponsor’s assessment of data quality. The subjects will be recruited at up to 8 Investigational Sites in 
the U.S. and divided into three age groups:   

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9.2. Subject Enrollment 
Subjects will be enrolled in the study once all eligibility requirements for the study have been met. 
Subjects who give informed consent for the protocol to undergo screening for eligibility are not 
considered enrolled and should not be enrolled until the screening is completed as indicated in Sections 
9.3, 9.4 and 10, and the subject is determined to meet all eligibility criteria.  
Study enrollment is accomplished by parent/ guardian signing the informed consent, age-appropriate 
assent form as required, and successfully passing the study inclusion /exclusion criteria. Subjects who sign 
informed consent, but are not enrolled, are considered screen failures. 
 
 Inclusion Criteria 
 Exclusion Criteria 
 
• 
4 to 8 years 
• 
9 to 12 years  
• 
13 to 18 years 
1) Pediatric Subjects (ASA PS I or II or III) aged 4 years to 18 years scheduled for procedures with sedation 
where the process of assessment will not interfere with the procedure, progress, or patient care 
Exclusion Criteria:  
1) Has severe contact allergies that may cause a reaction to standard adhesive materials found in pulse 
oximetry sensors, ECG electrodes, respiration monitor electrodes, or other medical sensors  
2) Known neurological disorder (e.g., epilepsy, the presence of a brain tumor, a history of brain surgery, 
hydrocephalic disorders, depression needing treatment with anti-depressive drugs, a history of brain 
trauma, hemiplegia, demyelinating disorders, cerebral palsy, congenital anomalies of the brain or spinal 
cord, or other known neurologic disorders)  
3) Severe developmental delay per assessment of investigator or report of parent/guardian 
4) Airway abnormalities 
5) Pregnancy; subjects of childbearing potential will have a urine screen for pregnancy before surgery 
6) If the process of assessment will interfere with the procedure or the progress of the procedure 
7) Taking psychoactive medications 
8) Taking any medications that may have an impact on the Central Nervous System (CNS) 
9) Planned use of any regional anesthesia; a local field block is not included in this exclusion and can be used 
at the discretion of the anesthesia provider 
10) Planned use of dexmedetomidine (Precedex) 
11) Refusal to participate in the study 

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10. Study Procedures  
10.1 Schedule of Events 
The Flowchart for enrollment and allocation to groups is shown in Figure 10. The Schedule of Events, Table 
5, summarizes the intervals and data collection procedures.  
Eligibility 
Assessment 
Training Case 
2-4
Randomized 
Standard 
Practice 
BIS 
Guided 
Age Group
4-8
Standard 
Practice 
BIS 
Guided 
Age Group
13-18
Analysis
Analysis
Not Analyzed
Excluded 
Excluded 
Age Group
9-12
BIS 
Guided 
Standard 
Practice 
Analysis
Not Analyzed
Not Analyzed
 
Figure 10: Study Flowchart 
10.2 Data Collection 
Table 5: Data collection and study procedure requirements at subject visits 
Study Tasks 
Baseline/ 
Enrollment 
Surgical Procedure 
PACU/ 
Discharge 
Randomization 
Induction and 
maintenance 
End of 
Surgery 
Baseline 
 

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Study Tasks 
Baseline/ 
Enrollment 
Surgical Procedure 
PACU/ 
Discharge 
Randomization 
Induction and 
maintenance 
End of 
Surgery 
Informed Consent 1 
x 
 
 
 
 
Inclusion/exclusion criteria review and 
confirmation of eligibility status 
x 
x 
 
 
 
Demographics 2 
x 
 
 
 
 
Medical History 3 
x 
 
 
 
 
Pre-operative Vital Signs 3 
x 
 
 
 
 
Procedure  
 
Randomization (before the procedure for group 
assignment) 4 
 
x 
 
 
 
BIS™ and Nellcor™ sensors placement  
 
 
x 
x 
 
BIS™, Nellcor™ and other digital data collection 
 
 
x 
x 
 
Standard surgical procedures 
 
 
x 
x 
 
ETSEVO concentration and other drug information   
 
 
x 
x 
 
Cardiovascular Variables 5 
x 
 
x 
x 
 
Event Markers and Assessments collection 6 
 
 
x 
x 
 
Anesthesia Airway Management 6 
 
 
x 
x 
 
Recovery  
 
Emergence 7 
 
 
 
x 
x 
Incidents of postop nausea and vomiting 7 
 
 
 
x 
x 
Vitals 7 
 
 
 
x 
x 
Wong-Baker FACES Scale 7 
 
 
 
x 
x 
Pediatric Anesthesia Emergence Delirium (PAED) 
7 
 
 
 
x 
x 
Modified Aldrete Score 
 
 
 
x 
x 

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Study Tasks 
Baseline/ 
Enrollment 
Surgical Procedure 
PACU/ 
Discharge 
Randomization 
Induction and 
maintenance 
End of 
Surgery 
Time of Readiness for PACU discharge 6,7 
 
 
 
x 
x 
Exit 
 
Reason for Study Exit 8 
x 
x 
x 
x 
x 
Safety  
 
Adverse Event Assessment 9 
x 
 
x 
x 
x 
Device Deficiency 9 
 
 
x 
x 
 
 
1) 
Written informed consent must be obtained before any study-specific evaluations, Section 10.5 
2) 
Demographic information, including sex, weight, height, age, ethnicity, race, as well as skin tone, will be recorded refer 
to Section 10.6. 
3) 
Relevant Medical History, including diagnosis and surgery type, will be collected, Section 10.7 
4) 
Randomization will be performed before the surgical procedure for group assignment refer to Section 10.8.  
5) 
Cardiovascular Variables (heart rate [HR]; systolic and diastolic blood pressure [BP] including hypotension; oxygen 
saturation; and temperature) refer to Section 10.9. 
6) 
For event markers and assessments, refer to Section 10.9 
7) 
For recovery data collection, refer to Sections 10.9. 
8) 
Details are included in Section 10.14..1 
9) 
Details are included in Section 12. 
10.3 Subject Screening  
All subjects that are considered for the study should be included on the study screening log. The reason 
for non-eligibility, as determined by the Investigator should also be recorded on the study screening log. 
The screening log serves as a method for Medtronic to assess selection bias in the trial. 
10.4 Prior and Concomitant Medications/Therapies 
There are medication restrictions in this study that include: psychoactive medications and any medication 
that may have an impact on the CNS. Subjects cannot be on any psychoactive medication and be included 
in the study. 
10.5 Subject Consent 
The Investigator or designee must obtain written informed consent before any clinical study related 
activity takes place. Before entry into the study, the Institutional Review Board (IRB) and Medtronic-

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approved ICF form, and the Health Insurance Portability and Accountability Act (HIPAA) Authorization 
Form (if not included within the ICF) (the US only) will be given to the parent or legal guardian of the 
potential subject.  
 
The Investigator or designee will fully inform the parent or legal guardian of the potential subject of all 
aspects of the clinical study that are relevant to the decision to participate in the clinical study. These 
activities may include the rights of the child as a subject in a research project, purpose and duration of 
the study, requirements of the subject during the study, potential risks and possible benefits associated 
with participation in this study. All items addressed in the ICF must be explained. The language used shall 
be as non-technical as possible and must be understandable to the parent/legal guardian. The 
parent/legal guardian must have ample time and opportunity to read and understand the ICF, to inquire 
about the details of the clinical study, and to decide whether or not to participate in the clinical study. The 
parent or legal guardian of a potential subject will be encouraged to discuss participation in the study with 
their support network (family, friends). All questions about the clinical study should be answered to the 
satisfaction of the parent/legal guardian.  
Neither the Investigator nor the investigation site staff shall coerce or unduly influence a subject and/or 
the parent/legal guardian to participate or to continue to participate in the clinical study. The informed 
consent process shall not waive or appear to waive the subject’s rights. 
 
The parent or legal guardian of the potential subject who then wishes to participate, and where the 
subject meets the inclusion/exclusion criteria, will be asked to sign and personally date the informed 
consent form on behalf of their child. Children of appropriate age will need to assent to the study and will 
be provided with an appropriate Institutional Review Board (IRB) approved Research Assent Form (RAF). 
The signed original informed consent is maintained in the Investigator’s records and a copy given to the 
parent/legal guardian.  
 
Medtronic will inform the Investigators whenever information becomes available that may be relevant to 
the subject’s confirmed participation in the clinical study. The Investigator or his/her authorized designee 
should inform the subject’s parent/legal guardian in a timely manner. 
 
Medtronic will revise the written ICF whenever new information becomes available that may be relevant 
to the subject’s confirmed participation in the clinical study. The revised information will be sent to the 
Investigator for approval by the IRB. After approval by the IRB, a copy of this information must be provided 
to the participating subjects, and the informed consent process, as described above, needs to be repeated. 
10.6 Enrollment 
A subject is considered enrolled when the consent process has been finalized. The date the subject (or the 
subject’s authorized/designated representative or guardian) signed the IC and Data Protection 
Authorization, as required by law, must be documented in the subject’s medical records. A log of all 

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subjects enrolled in the study should be maintained.  Enrollment can be a stand-alone visit or can occur 
on the same day as the baseline visit. Once consent is obtained, report adverse events/deaths, study 
deviations and subject exits as they occur. 
10.7 Baseline 
Once ICF is signed, the following will be obtained: 
10.8 Randomization and Treatment Assignment 
Prior to Randomization, 2 - 4 subjects from each site will be consented and enrolled. The data will be used 
to train on the new technology use, and to review the quality of the data collection, refer to Section 10.2. 
 
Subjects are eligible for randomization assignment after study enrollment and verification of eligibility 
criteria. Subjects will be randomized in a 1:1 fashion to the BIS™ group or standard practice group using 
the RDC electronic system. Randomization schedules will be created by a Medtronic statistician, and 
randomization assignments will be automatically populated on the Randomization e-CRF after subject 
consent and eligibility verification have been entered in RDC. The randomization schedule will be stratified 
by age group and the study site to ensure 1:1 randomization within each study site. 
10.9 Surgical Procedure and Data Collection   
The surgical procedure will be conducted per Standard of Care (SOC). Subjects are being recruited with a 
planned maintenance time of 30 minutes or greater. If the subject’s maintenance time is less than 25 
minutes, the data will continue to be collected, but will not be included in the final data analysis and the 
subject will be replaced by an additional enrolled subject. 
10.9.1 
 Prior to Induction 
Prior to induction, subjects may be pre-medicated with Midazolam (Versed) per institutional guidance. 
The subject taken into the operating room, and anesthesia delivery system will be applied per institutional 
guidance. 
• 
Demographics (race, ethnicity, sex, height, weight, skin tone, )  
• 
Medical history, including diagnosis for surgery and the American Society of Anesthesiologist (ASA) physical 
status classification system, is used to evaluate the degree of a patient's "sickness" or "physical state.” Only 
subjects with ASA Physical status I, II or III will be enrolled 
• 
Concomitant Medications, including the history of prescription and over the counter medication, will be 
carefully noted and recorded within 1 month before the surgery. Medication name, indication for use, 
dose, frequency, route of administration start/stop date 
• 
Cardiovascular Variables - Heart Rate, Systolic, mean, and Diastolic Blood Pressures, Respiratory Rate, 
Oxygen Saturation (SpO2)  

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10.9.1.1 
BIS™ Sensor Application 
Prior the induction of anesthesia, all subjects will have an age-appropriate BIS™ sensor. The sensor, BIS™ 
pediatric or BIS™ QUATRO Sensor, will be selected by the clinician based on the size of the forehead and 
space available on the forehead. The sensor will be placed on the forehead after cleaning the site with an 
alcohol wipe per the IFU recommendation.  The sensor type will be captured on eCRFs. 
10.9.1.2 Pulse Oximeter Sensor Application 
The age-appropriate pulse oximeter sensor will be applied to the subject per sensor IFU. A left or right 
index finger is the preferred sensor site. Alternatively, the sensors can be applied to a smaller finger, 
thumb, or big toe. The sensor type, position and side will be recorded on the eCRF. 
 
If the subject is uncooperative when awake, the BIS™ sensor will be placed after adequate sedation has 
been achieved with the use of pre-medication drugs. 
 
The choice of pre-medication, dose, and time of administration will be determined by the site 
anesthesiologist and will not be altered for the study, but the use of these drugs will be recorded on the 
eCRF. 
10.9.2 
Induction 
Anesthesia will be induced with sevoflurane alone, or a combination of sevoflurane and nitrous oxide 
(N2O) in 100% oxygen in both groups. If the nitrous oxide is used, it will be discontinued after the 
placement of a tracheal tube or laryngeal mask (LMA), or another airway management. If necessary, a 
neuromuscular blocking agent will be used to facilitate endotracheal intubation. The choice of medication, 
dose, and time of administration will be determined by the site anesthesiologist and will not be altered 
for this study, but the use of these drugs will be recorded on the eCRFs.  If the subject is in need of a 
regional block for pain management following the procedure, this block should be placed once skin closure 
is complete and prior to extubation. This block cannot be placed prior to skin closure. Subjects with the 
planned use of any regional anesthesia are excluded from this study, however if any regional anesthesia 
becomes necessary for the subject during the course of the surgical procedure, data will continue to be 
collected on the subject, however the data will not be included in the data analysis and the subject will be 
replaced by an additional enrolled subject. The use of dexmedetomidine (Precedex) is prohibited from 
being used in this study. If it becomes necessary to use this medication during the course of the surgical 
procedure, data will continue to be collected on the subject, however the data will not be included in the 
data analysis and the subject will be replaced by an additional enrolled subject. 

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10.9.3 
Maintenance 
10.9.3.1 
Training Group 
A training group, comprising of the first 2 - 4 subjects at each site will be enrolled to train the site team 
on the new technology and to determine the quality of data collection before randomization.  
 
Sevoflurane administration will be at the discretion of the anesthesiologist using clinical signs and 
cardiovascular changes to adjust anesthetic concentration. The end-tidal sevoflurane concentrations will 
be continuously recorded. Fentanyl, propofol, and/or morphine will be administered at the discretion of 
the anesthesiologist for example, morphine at 1.5 mcg/kg at induction and 0.75 mcg/kg every 30 minutes 
in accordance with usual clinical indications.  
 
For the SP group, sevoflurane, fentanyl, propofol, and/or morphine will be administered at the discretion 
of the anesthesiologist for example, fentanyl and morphine at 1.5 mcg/kg at induction and 0.75 mcg/kg 
every 30 minutes in accordance with usual clinical indications.   
 
The clinician will be blinded to the BIS™ values, and the BIS™ value is not used to guide the conduct of the 
anesthetic. The SQI number will be visible to the anesthesiologist during the case to capture a good quality 
signal. The details on SQI monitoring will be provided to the study site. 
10.9.3.2 Standard Practice Group 
In this group, sevoflurane administration will be at the discretion of the anesthesiologist using clinical 
signs and cardiovascular changes to adjust anesthetic concentration. The end-tidal sevoflurane 
concentrations will be continuously recorded. Fentanyl propofol, and/or morphine will be administered 
at the discretion of the anesthesiologist, for example, morphine at  1.5 mcg/kg at induction and 0.75 
mcg/kg every 30 minutes in accordance with usual clinical indications.  
 
The clinician is blinded to the BIS™ values, and the BIS™ value is not used to guide the conduct of the 
anesthetic. The SQI number will be visible to the anesthesiologist during the case to capture a good quality 
signal. The details on SQI monitoring will be provided to the study site. 
10.9.3.3 BIS™ Guided Group 
In the BIS™ group, sevoflurane will be adjusted to achieve a target BIS™ values of 45 – 60 during 
maintenance of anesthesia and BIS™ values of 60 – 75 beginning of skin closure. Subjects with BIS™ values 
that are outside of the specified range of 45 – 60 during maintenance of anesthesia for >35% of the 
maintenance duration will be considered a protocol deviation and the subject will be excluded from the 
final data analysis and will be replaced by an additional subject. The excluded subject will continue to be 
monitored for any safety events and the clinical will ensure that medical care is provided should a safety 
event occur. Data from the excluded subject will be acknowledged in the final study report but will not be 

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included in the primary statistical analysis. The exception to this exclusion is any data that is outside of 
the specified range of 45 – 60 as a result of the anesthesiologist titrating medications as a result of clinical 
signs or cardiovascular changes defined above.  Additionally, data points will be excluded if significant 
artifact is present or if the sevoflurane concentration or BIS™ value is missing.  
 
At the completion of the surgery, and after confirmation of the return of neuromuscular function, 
sevoflurane will be discontinued, and discontinuation time will be recorded, and as applicable, extubation 
will be performed when the patients demonstrate the purposeful movement, facial grimace, or eye-
opening to jaw thrust.  
10.9.4 
Monitoring and Cardiovascular Variables 
Monitors for the collection of variables such as pulse oximeter, non-invasive blood pressure (NIBP), 
electrocardiography, and skin temperature will be applied per institutional guidance. The standard 
monitoring procedures will be conducted per institutional recommendation and are not being mandated 
by the protocol. The de-identified digital copies of these files will be provided to Medtronic as available.   
Pre-surgical Cardiovascular variables (heart rate [HR]; systolic and diastolic blood pressure [BP] including 
hypotension; oxygen saturation; and temperature), and BIS™ (for the BIS™ group) will be recorded at 
baseline preferably before administering any pre-medication or sedatives. Cardiovascular variables will 
be monitored during the surgery, and any abnormal cardiovascular parameters and times will be recorded 
in the medical record. The de-identified digital copies of these files will be provided to Medtronic as 
available.   
10.9.5 
Event Markers and Assessments 
During the case, the time of events listed below will be recorded. 
The end-tidal anesthetic gas concentration will be time-locked to the BIS™ system recordings. End-tidal 
sevoflurane, oxygen, and nitrous oxide concentrations will be downloaded from the anesthetic monitoring 
device, and de-identified digital copies will be provided to Medtronic. 
 

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Any time end-tidal sevoflurane concentration (ETSEVO) is increased or decreased or opioid or other 
medication is given, the event and time will be marked on the eCRFs. Also, if any changes to the dose or 
administration regimen are needed, these changes will be noted on the eCRF. 
Time and values of BIS™, ETSEVO concentration (%) and other medication, FiO2(%) and EtO2(%), EtCO2(%) 
will be recorded at the following time intervals: 
• 
Baseline  
• 
Study start 
• 
At IV placement, as applicable 
• 
Start of induction 
• 
Start of N2O, as applicable 
• 
Start of sevoflurane 
• 
At Anesthesia Airway Management (AAM)  
• 
AAM change (including type of AAM) 
• 
At any airway reflex (coughing, choking, layngospasm) 
• 
Every 15 min after airway management 
• 
At all drug administration (as applicable) 
• 
N2O off (as applicable) 
• 
Start of the surgery/procedure 
• 
Skin incision, if applicable 
• 
End of surgery/procedure (or skin dressing or cast or splint applied or abdominal block)  
• 
Skin closure, if applicable 
• 
Sevoflurane off 
• 
Termination of all anesthesia 
• 
Extubation 
• 
Physician Awakening subject, if applicable 
• 
Time of emergence (if occurs in OR) 
• 
End of study (removal of device)  
• 
15 min post dexmedetomidine administration, if applicable 
• 
Time moved to PACU 
 

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10.9.6 
Recovery 
PAED, Wong-Baker FACES Pain Scale, and Modified Aldrete Score data will be recorded in source every 
15 minutes. Raw data but total scores for the highest amount of delirium from the PAED, the highest 
amount of pain from the Wong-Baker FACES Pain Scale and the least ready for discharge Modified 
Aldrete Score raw data will be entered in to the CRF. The final raw data and total scores for the PAED, 
Wong-Baker FACES Pain Scale and Modified Aldrete Scale will be entered into the eCRF.  
 
10.9.6.1 
Presence of laryngospasms, coughing, choking 
Presence of laryngospasms, coughing, choking as indicated by the anesthetist, if any present, time, and 
treatment course will be documented.   
10.9.6.2 Pediatric Anesthesia Emergence Delirium (PAED) 
Both groups will be assessed using the Pediatric Anesthesia Emergence Delirium (PAED) scale [1].  The 
PAED is an observational scale that has been validated in children to detect and measure the severity of 
hyperactive emergence delirium upon awakening from anesthesia. The scale includes 5 items: 1) Child 
makes eye contact with the caregiver, 2) child’s actions are purposeful, 3) child is aware of his/her 
surroundings, 4) child is restless, 5) child is inconsolable. The scale is included in Appendix A. The time 
and treatments/conmedications  given for delirium and will be documented. 
Subject recovery will be continuously after the termination of anesthesia for presence of coughing, 
choking, laryngospasms, and emergence.  
Emergence is defined as the time when any of the following first occurred:  
• 
eyes open spontaneously,  
• 
crying or phonating, or  
• 
purposeful movements.  
The time of emergence, time subject moved to PACU, and time of readiness for discharge will be 
recorded. The time of these assessments will be captured in medical records, source, and recorded on 
the eCRFs. 
All subjects will be assessed at 15-minute intervals: 
• 
Pediatric Anesthesia Emergence Delirium (PAED)  
• 
Wong-Baker FACES Pain Scale (when subject is awake) 
• 
PACU discharge readiness - Modified Aldrete Score 

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10.9.6.3 Wong-Baker FACES Scale 
The Wong Baker FACES pain scale is an instrument validated for ages 3+ to measure pain, by selecting a 
number on an ordinal 0-10 scale (“0” being no pain and “10” being the worst pain ever). Subjects will be 
instructed to indicate their degree of pain prior to being discharged from the PACU. The Wong-Baker 
FACES Scale will be administered when the subject is awake and able to perform the assessment. For more 
information, refer to Appendix B. 
10.9.6.4 Modified Aldrete Score 
End of surgery to post-anesthesia care unit (PACU) discharge readiness will be assessed using the Modified 
Aldrete Score that examines the following five criteria: motor activity, respiration, blood pressure, 
consciousness, and color [15, 16]. Before a subject can be safely discharged from the PACU, a score of 12 
out of 16 points based on the PACU standard discharge criteria will be achieved. The time and score of 
PACU discharge reediness will be recorded. The scale is included in Appendix C. 
10.9.7 
Safety Monitoring 
The choice of sedative drugs, dose, and route of administration will be based on clinical indications as 
judged by the Attending Physician and will not be changed for the purposes of the study. The BIS™ monitor 
will not be used in situations where the placement of the probe will interfere with a procedure, cause 
scan artifacts, or where the presence of a metal monitor is contraindicated (e.g., MRI scans). Therefore, 
we believe there is only a minimal increase in risks from participating in the study. This risk relates to the 
possibility of developing irritation to the skin at the site of sensor placement.  
Subjects will be monitored for Adverse Events, Unanticipated Adverse Device Effects, Serious Adverse 
Events, and Device-Related Adverse Events from BIS™ sensor applications through the BIS™ sensor 
removal. 
Any study procedures may be discontinued for the subject’s safety. For patient safety, modifications to 
the procedure steps will be left to the judgment of the Principal Investigator.  
 Assessment of Efficacy 
Refer to Section 14. 
10.11 Assessment of Safety 
For safety analyses, adverse events will be summarized using frequency counts and percentages, refer to 
Section14.. Descriptive statistics will be provided by event type, severity, and relationship to study 
procedures and devices. Individual listings of adverse events, including event type, start date, duration, 
severity, and device-relatedness, will be provided as appropriate. Adverse events occurring during the 
procedure or 48 hours after the procedure will be recorded. For AEs and AE reporting requirements, refer 
to Section 12. 
10.12 Recording Data 
The study will utilize the electronic Case Report Forms (eCRFs) in a database provided by the Sponsor.  

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eCRF completion may be delegated by the Principal Investigator (documented on the Delegated Task List) 
to other study personnel, but the Principal Investigator remains responsible for the accuracy and integrity 
of all data entered in eCRFs. The Principal Investigator or delegated Sub-Investigator is required to 
approve all data on eCRFs via electronic signature. 
 
Additional details regarding procedures used for data review, database cleaning, issuing and resolving 
data queries, and identification of steps for creation, modification, maintenance, archiving retrieval or 
transmission of source data via any computerized systems will be provided in the study-specific Data 
Management Plan (DMP). 
10.13 Deviation Handling 
The Investigator is required to conduct this study in accordance with the protocol, Good Clinical Practice 
(GCP), Institutional Review Board (IRB) requirements, and applicable regulations. The Investigator is not 
allowed to deviate from the above-mentioned documents except under emergency circumstances to 
protect the rights, safety, and well-being of human subjects. 
A study deviation is defined as an event when the investigator or site personnel did not conduct the study 
according to the protocol or the clinical trial agreement. 
The Investigator is required to obtain prior approval from the sponsor and IRB before initiating deviations 
from the Clinical Investigation Plan, except where necessary to protect the life or safety and physical well-
being of a subject in an emergency. Such approval will be documented in writing and maintained in the 
study investigator files.  
Major deviations are defined as deviations with respect to: 
• 
Patient informed consent procedure; 
• 
Patient eligibility criteria; 
• 
Late reporting of Serious Adverse Event /Serious Adverse Device Effect /Unanticipated Adverse 
Device Effect (for reporting refer to Section12). 
Deviations will be recorded at the site and reported to Medtronic on the eCRF and via email to the study 
manager. The Protocol Deviation eCRF document shall be signed and dated by the Investigator or his 
authorized designee. At a minimum, the following information will be recorded: 
• 
identification of the Investigator and site 
• 
description of deviation 
• 
date of occurrence 
• 
reason for the deviation 

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• 
patient identifier, if associated with the event 
 
Deviations will be entered into a database to allow a comprehensive review on a regular basis for 
identifying trends that warrant additional preventive or corrective actions to mitigate further occurrence. 
Clinical study management at Medtronic shall conduct this review. Repetitive or serious investigator 
compliance issues may result in the need to initiate a corrective action plan, and in some cases, freeze 
enrollment or ultimately terminate the Investigator’s participation in the clinical study. 
Study deviations must be reported to Medtronic, regardless of whether medically justifiable, pre-
approved by the study leader (see contact details section) or taken to protect the subject in an emergency.  
In the case that the deviation involves a failure to obtain a subject’s informed consent or is made to 
protect the life or physical well-being of a subject in an emergency, the deviation must be reported to the 
IRB as well as the study leader as soon as possible after the occurrence of the event. Reporting of all other 
study deviations should comply with IRB policies and/or local laws. 
The Investigator shall adhere to IRB requirements and procedures for reporting study deviations. 
All deviations from the CIP shall be included in the final report. 
10.14 Subject Exit, Withdrawal or Discontinuation  
The subject’s parent and/or legal guardian or the subject has the right to withdraw from the study at any 
time and for any reason without sanction, penalty or loss of benefits to which the subject is otherwise 
entitled, and without jeopardizing their future medical care. The Investigator may withdraw the subject 
at any time to protect the health, safety, or welfare of the subject. Every effort should be made to collect 
the status of any ongoing adverse events, at a minimum.  
 
If the subject discontinues participating in the study before completing the study requirements, the 
reason for withdrawal will be recorded in the subject’s study records and eCRF. 
 
If withdrawal from the study is due to problems related to the investigational device safety or 
performance, the Investigator shall ask for the subject’s permission to follow his/her status outside the 
clinical study. 
There are many scenarios in which a subject may exit the study. The following terms are used for 
withdrawal and completion: 
• 
When and how to withdraw subjects from the study product treatment 
• 
The type and timing of the data to be collected for withdrawn subjects 
• 
Whether and how subjects are to be replaced 
• 
The follow-up for withdrawn subjects. 

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• 
Screen Failure: Subject did not meet the study inclusion/exclusion criteria;  
• 
Study Withdrawal: Removal from the study after enrollment by either subject /legal guardian, PI, 
or Sponsor, or technical problems;  
• 
Study Complete: Completion of all study related activity by the subject; 
• 
Other: protocol deviation leads to replacement of subject 
10.14.1 
Study Exit 
A study exit eCRF is required for all subjects. Prior to exiting a subject from the study, it is recommended 
to follow the subject until all ongoing system and/or procedure related AEs are resolved or unresolved 
with no further actions planned.  Following exit, subjects will continue to receive standard medical care.  
Upon exiting from the study, no further study data will be collected, or study visits will occur for the 
subject.  All data available through the time of the subject’s exit will be used for analysis.  
Subjects are urged to remain in the study as long as possible but may be exited from the study for any of 
the following situations: 
• 
Study completed 
• 
Subject did not meet inclusion/exclusion criteria  
• 
Subject did not provide consent or data use protection authorization 
• 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another geographic 
location)  
• 
Investigator deems withdrawal necessary (e.g., medically justified, inclusion/exclusion 
criteria not met, failure of subject to maintain adequate study compliance)  
The following information is required to be collected at study exit: 
• 
Reason for exit 
If discontinuation is because of safety, the subject shall be asked to be followed for collecting safety data 
outside the clinical investigation. 
10.14.2 
Subject Chooses to Exit (i.e. Revokes Consent) 
A subject can withdraw from the study at any time. If the subject wishes to exit from the study (i.e. the 
subject revokes consent), the study site is required to document the reason for exit on the Exit CRF. In 
addition, study sites shall follow the regulations set forth by the governing IRB. If possible, the following 
data should be collected prior to subject withdrawal: 
• 
Reason for exit 

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10.14.3 
Investigator Withdraws Subject 
No subjects should be withdrawn by investigators unless compelling medical justification is present. It is 
recommended investigators discuss any withdrawals with the study team prior to withdrawing subjects. 
If the subject was randomized, it is preferred to keep the subject in the study and perform study 
procedures/collect data to the extent possible. If an Investigator Withdrawal is necessary, the following 
data should be collected prior to subject withdrawal if possible: 
• 
Reason for subject withdrawal 
11. Risks and Benefits 
11.1. Potential Risks 
Risks to participation are primarily physical. There are no social, economic, legal, long-term psychological, 
or other risks that have been identified. Risks under this protocol relate to both study devices and study 
procedures. We believe that the risks from the device(s) are in keeping with the definition of non-
significant risk devices (NSR). Further, the devices in this study are non-invasive, and the clinical protocol 
design is minimal risk to the subject. No treatment or treatment decisions will be made during the course 
of this study. Following is a list detailing potential risks from study devices and the clinical protocol.   
11.1.1 
BIS™ Sensor Risks 
The BIS™ Sensor is applied directly to the patient’s skin to enable recordings of electrophysiological (such 
as EEG) signals. The sensor will be used as per IFU. The sensors used in this study may expose subjects to 
the following risks:  
For more information on Sensor warnings and cautions, refer to Sensor IFU. 
11.1.2 
BIS™ Monitoring System Risks  
BIS™ Monitoring System will be used per IFU. For more information on warnings and cautions, refer to 
IFU. 
• 
Minor discomfort, allergic reaction, or skin irritation (such as redness, itching) at the sensor application 
site is probable but is usually self-limited within hours.  
• 
Pressure points/ injury in application areas are possible but anticipated to be rare due to the short 
duration of the study. Care in the application and removal of the sensors is advised. Skin reactions will be 
observed during and after the study procedures.  
• 
Electric shock is very rare, and the product design and testing ensure insulation and ground fault 
detection.  
• 
Burn to the skin (due to a small amount of heat generated) is a rare unanticipated risk, and not likely due 
to the short duration of the study.  

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11.1.3 
Pulse and Tissue Oximetry Sensor 
Pulse and Tissue Oximetry Sensor placement involves positioning pulse and tissue oximetry sensors on 
the subject per the IFUs.  
The sensors may be warm to the touch. Under normal operating conditions (no fault conditions), the 
sensors are not expected to overheat. If the sensors are too warm, they will be removed immediately.  
The sensors exert a minimal amount of pressure. Sensors may leave minor impressions at the sensor 
application site, which should fade and resolve within the day. They should not cause discomfort. If the 
sensors are too uncomfortable, they will be removed.   
Adhesive sensors may cause some irritations to the skin in some subjects. Typical skin irritations present 
with redness of the skin, and in some cases of sensitivity, an allergic reaction can occur. Removal of the 
sensor may cause pulling of the skin or hair, and this can be felt as pain. The risk in the use of oximetry 
sensors is believed to be minimal. 
A heating pad or hot water bottles may be used on the hands to improve circulation. The subject may 
experience some mild discomfort if the water is too warm. To minimize the discomfort, the subject will 
be asked if the heating is too warm, it will be turned on the lowest level possible for comfort, removed or 
additional separation will be used between the heater and the site for comfort. 
11.1.4 
General Anesthetics  
There are some risks associated with taking general anesthetics, but they are relatively safe when 
administered correctly. General anesthesia will be administered per institutional guidance. All Subjects 
will be monitored by health care professionals closely for the effects. The most common side effects of 
general anesthesia include sore throat due to the breathing tube, nausea, vomiting, dizziness, bruising, or 
soreness from the IV drip, shivering and feeling cold, difficulty passing urine. These may occur despite the 
best efforts to avoid them.  
Also, when placing a breathing tube, there is a small risk that the anesthesia provider can damage the 
subject’s teeth. This risk increases if the subject has loose teeth or other dental problems. With any 
medication given, the Subject could have an allergic reaction. Although rare, unexpected severe 
complications with anesthesia can occur and include, but not limited to, the remote possibility of 
infection, bleeding, drug reactions, blood clots, loss of sensation, loss of limb function, paralysis, stroke, 
brain damage, heart attack or death. The anesthesiologist will be present to minimize all risks related to 
anesthesia. 

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11.2. Potential Benefits 
There are no medical benefits to the subjects who participate in this study. There is, however, the 
potential for benefiting future subjects should this study enable the development of improved medical 
monitoring devices. 
11.3. Risk-Benefit Rationale 
Medtronic has determined that this is a study of a “non-significant risk device” due to the nature of the 
devices being tested. Utilizing the FDA criteria1,2 listed below to distinguish between significant and non-
significant risk devices, Medtronic has determined that: 
 
The potential risks of these devices have been assessed and are not greater than those of currently 
approved and marketed devices of the same type (e.g., pulse and tissue oximeters, EtCO2 monitors, non-
invasive blood pressure monitors, ECG or respiration monitors). Society may benefit from more accurate 
medical monitors. 
 
Medtronic requests that the reviewing IRB indicates its agreement with this determination of non-
significant risk device in its letter of approval for this study.  
11.4. Risk Determination 
Medtronic has determined that this is a study of “non-significant risk”. 
 
1 21CFR812.2 (b)(1)(ii) and 21CFR812.3(m) 
2 Information Sheet Guidance For IRB/EC , Clinical Investigators, and Sponsor. Significant Risk and Non-significant Risk Medical Device Studies/  
January 2006/UMC126418 
• 
The device under investigation is not intended as an implant and does not present a potential for 
serious risk to the health, safety, or welfare of a subject; 
• 
The device under investigation is not purported or represented to be for use supporting or sustaining 
human life and does not present a potential for serious risk to the health, safety, or welfare of a 
subject; 
• 
The device under investigation is not for the use of substantial importance in diagnosing, curing, 
mitigating, or treating disease, or otherwise preventing impairment of human health, and does not 
present a potential for serious risk to the health, safety, or welfare of a subject; and 
• 
The device under investigation does not otherwise present a potential for serious risk to the health, 
safety, or welfare of a subject. 

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12. Adverse Events and Device Deficiencies 
12.1 Adverse Events 
AE definitions are provided in Table 6.  
 
AE information will be collected throughout the study from the enrollment through study exit.  
A list of anticipated adverse events and risks that are expected in nature is included in Section 10.  
 
Reporting of these events to Medtronic will occur via prompt email and the AE eCRF. Each event must be 
reported separately. Documented pre-existing conditions are not considered AEs unless the nature or 
severity of the condition has worsened.  
 
For AEs that require immediate reporting (see Table 7), initial reporting must be done by email, phone, , 
and then on the eCRF completing as much information as possible. The completed AE eCRF must be 
submitted to Medtronic as soon as possible.   
Any medication/treatment associated with the treatment of an AE must be reported  
All AEs considered at least possibly related to the study will be followed until resolved, stabilized, and/or 
returned to baseline. 
Medtronic will immediately conduct an evaluation of reported events. Table 5 shows event reporting 
requirements. At a minimum, the following information will be recorded: 
 
Table 5: Definition of Adverse Events and Device Deficiencies 
General 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device. 
NOTE 1: This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
• 
A description of the event 
• 
The date of event onset 
• 
The relatedness of the event to the device 
• 
Actions are taken as a result of the event 
• 
The outcome of the event 

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NOTE 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse 
of the investigational medical device. 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety 
or performance. 
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
Relatedness 
Device Related 
An AE that results from the presence or performance (intended or otherwise) of the device. 
Procedure Related 
An AE that occurs related to the procedure. 
Seriousness 
Serious Adverse Device 
Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event. 
Serious Adverse Event (SAE) 
An adverse event that 
a) 
led to death, 
b) 
led to serious deterioration in the health of the subject, that either resulted in 
1) 
a life-threatening illness or injury, or 
2) 
a permanent impairment of a body structure or a body function, or 
3) 
in-subject or prolonged hospitalization, or 
4) 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) 
led to fetal distress, fetal death or a congenital abnormality or birth defect. 
NOTE:  Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
Unanticipated Adverse 
Device Effect (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the CIP or application (including a supplementary 
plan or application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety or welfare of subjects. 

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Complication 
An adverse event that includes the following is considered a complication: 
• 
Results in death, 
• 
Involves any termination of significant device function, or 
• 
Requires an invasive intervention 
 
Non-invasive (21 CFR 812.3 (k)): when applied to a diagnostic device or procedure, means one 
that does not by design or intention: 
• 
Penetrate or pierce the skin or mucous membranes of the body, the ocular 
cavity, or the urethra, or 
• 
Enter the ear beyond the external auditory canal, the nose beyond the nares, 
the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina 
beyond the cervical os 
Where “penetrate” means: to pass, extend, pierce, or diffuse into or through 
something; to enter by overcoming resistance; to gain entrance to, and “pierce” 
means to force a way into or through something 
 
NOTE (FDA): Blood sampling that involves simple venipuncture is considered noninvasive, and 
the use of surplus samples of body fluids or tissues that are left over from samples taken for 
non-investigational purposes is also considered noninvasive. 
Observation 
Any AE that is not a complication. 
 
NOTE 1: Only system or procedure related AEs will be classified as “Complication” or 
“Observation” 
 
 Reporting of Adverse Events  
Principal Investigator must report applicable events and product deficiencies to Medtronic and where 
appropriate an IRB or regulatory authority.  At a minimum, the following information will be recorded: 
Study Contact Information: 
Clinical Affairs 
Medical Affairs 
• 
A description of the event 
• 
The date of event onset 
• 
The relatedness of the event to the device 
• 
Actions are taken as a result of the event 
• 
The outcome of the event 

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Ami Stuart, PhD, MSCI 
Clinical Study Manager  
Medtronic 
6135 Gunbarrel Avenue 
Boulder, CO 80301 
Phone: (80i) 793-4800 
ami.stuart@medtronic.com 
Sam Ajizian, MD 
Chief Medical Officer- Patient Monitoring 
Medtronic 
350 Cedar Trail 
Winston-Salem, NC 27104 
Phone: (336) 749-8557 
Sam.ajizian@medtronic.com 
12.2.1 Adverse Event and Device Deficiency Classification 
All AE and DD will be reviewed by a Medtronic representative. AEs will be classified according to the 
definitions provided.  
Upon receipt of AE at Medtronic, a Medtronic representative will review the AE/DD for completeness 
and accuracy and when necessary will request clarification and/or additional information from the 
Investigator. Medtronic will utilize MedDRA for Regulatory Activities, to assign a MedDRA term for each 
AE based on the information provided by the investigator.  
Regulatory reporting of AEs and DDs will be completed according to local regulatory requirements. Refer 
to Table 5 for a list of required investigator and Medtronic reporting requirements and timeframes. It is 
the responsibility of both to abide by any additional AE reporting requirements stipulated by the EC 
responsible for oversight of the study. 
For emergency contact regarding a UADE, USADE, SAE and/or SADE, contact a study representative 
immediately (refer to the study contact list provided in the study site’s study documents 
binder/investigator site file or refer to the Sponsor contact information provided on the title page). 
AEs and Deaths will be classified according to the standard definitions as outlined below: 
Table 6: Adverse Event Classification Responsibilities 
What is classified?  
Who classifies? 
Classification Parameters 
Relatedness 
Investigator 
Device, Procedure  
Sponsor 
Device, Procedure, BIS™ System components 
Seriousness 
Investigator 
SAE, DD with SADE potential 
Sponsor 
SAE, UADE/USADE, Complication or Observation (for all procedure related 
adverse events), DD with SADE potential  
Diagnosis 
Investigator 
Based on presenting signs and symptoms and other supporting data 
Sponsor 
MedDRA term assigned based on the data provided by Investigator 
12.2.2 Adverse Event and Device Deficiency Reporting Requirements 
Regulatory reporting of AEs and DDs will be recorded and reported according to local regulatory 
requirements. It is the responsibility of the Investigator and the sponsor to abide by the AE reporting 
requirements stipulated by local law and the study site’s IRB.  

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Table 7: Reporting Requirements for Events 
Serious Adverse Device Effects (SADE), including Unanticipated Adverse Device Effect (UADE): 
Investigator submits to: 
 
Medtronic 
Within 24 hours after the investigator first learns of the event. 
Regulatory Authority 
As per local reporting requirements.  
IRB 
Submit to IRB per local reporting requirement. 
Sponsor submits to: 
 
Regulatory Authorities  
Reporting timeframe as per local requirement. 
IRB 
Submit to IRB per local reporting requirement. 
Serious Adverse Events (SAE) 
Investigator submits to: 
 
Medtronic 
Within 24 hours after the investigator first learns of the event. 
Regulatory Authority 
As per local reporting requirements.  
IRB 
Submit to IRB per local reporting requirement. 
Sponsor submits to: 
 
Regulatory Authorities  
Reporting timeframe as per local requirement. 
IRB 
Submit to IRB per local reporting requirement. 
Adverse Device Effects (ADE) 
Investigator submits to: 
 
Medtronic 
Within 24 hours after the investigator first learns of the event. 
Sponsor submits to: 
 
Regulatory Authority 
As per local reporting requirements.  
IRB  
Submit to IRB per local reporting requirement. 
Sponsor submits to: 
 
Regulatory Authorities 
Reporting timeframe as per local requirement 
IRB  
Submit to IRB per local reporting requirement. 
All other AEs 
Investigator submits to: 
 
Medtronic 
Submit as soon as possible, but no later than within 10 working days after the investigator 
first learns of the event. 
Regulatory Authority 
As per local reporting.  
IRB  
Submit to IRB per local reporting requirement. 
Device Deficiency with SADE potential 
Investigator submits to: 
 
Medtronic 
No later than 48 hours after the investigator first learns of the event. 
Regulatory Authorities 
As per local reporting requirements. 
IRB  
As per local reporting requirement. 
Sponsor submits to: 
 
Regulatory Authorities 
As per local reporting requirements. 
IRB  
As per local reporting requirement. 
All other Device Deficiencies 
Investigator submits to 
 

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Medtronic 
No later than 48 hours after the investigator first learns of the event. 
Regulatory Authorities 
As per local reporting requirements. 
IRB 
As per local reporting requirement. 
Sponsor submits to: 
 
Regulatory Authorities 
As per local reporting requirements. 
IRB 
As per local reporting requirement. 
 Foreseeable AE or SAE 
The information provided in this section pertains to foreseeable adverse events that may be observed in 
this study and may collectively assist in identifying those events for a given device or therapy that are 
unexpected in nature. The foreseeable adverse events information consists of two parts: 1) adverse 
events reported in published literature, and 2) additional foreseeable adverse events. Evaluation of 
potentially anticipated events, adverse device effects observed in previous clinical studies, and reported 
events in literature may be used in combination with device labeling, current event reporting information, 
and other published data to assess for an unexpected occurrence.  
12.3.1 Surgical Procedure 
The study will be collecting data during the SOC surgical procedure; therefore, standard adverse events 
associated with a surgical procedure may be experienced (e.g., anesthesia complications, injury, 
infections, bleeding, exacerbation of pre-existing conditions, healing complications, etc.). Data from peer-
reviews literature indicates that approximately 10% of the surgical patients had at least one AE related to 
the surgical procedures or the hospital environment [18] [19]. These events are not necessarily related to 
the study devices. In this study, the surgical procedure will be performed per SOC, and events related to 
the surgical procedure will not be captured.  
All device and anesthesia management related to adverse events will be captured.  
12.3.2 Anesthesia Management Adverse Events 
During anesthesia, the events listed below will be captured: 
• 
Hypotension and hypertension >20% from baseline, cardiac arrest or clinically significant changes 
in Heart Rate or Blood Pressure >20% from baseline  
• 
The respiratory complications involving: 
o 
laryngospasm  
o 
bronchospasm  
o 
desaturation (SpO2<90%, of any duration)  
o 
hypercarbia (PCO2=55mmHg) 
• 
Events related to movement, grimacing, eye opening, tearing, sweating, mydriasis 

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12.3.3 BIS™ Sensor 
Potential risks associated with the BIS™ sensor, as well as risk minimization, are discussed within Section 
11..  The use of the BIS™ sensors may cause minor discomfort, an allergic reaction or skin irritation such 
as redness, itching, swollenness and redness, water-filled blister, and reddened scar tissue. These events 
will be collected during the study.  
12.3.4 Adverse Events Reported in Literature 
Potential adverse events and patient complications associated with BIS™ sensor reported in the literature, 
including skin integrity/pressure sores, rash, ecchymosis/heat wounds.  
Skin integrity and reactions will be assessed just after sensor removal. All mild events that resolve within 
48 hours after sensor removal are anticipated and will not be considered as reportable AE. If pronounced 
erythema and papules, or vesicular eruption are visible, on the subject’s skin after sensor removal or if 
the subject requires any medical intervention related to the skin event then this event will be considered 
as AE. For more events and risk assessments, refer to Section 10.  
In addition, the skin assessment will be reviewed by the Clinical Study Manager (CSM) and Medical Advisor 
in accordance with Clinical Safety Management and Potential complaint Plan. If the sponsor assessment 
of event classification differs from those opinions of the reporting investigator, the CSM communicates 
both opinions to the Site and Medtronic Complaint Handling Unit as needed.  
 Product Complaint Reporting 
The reporting of product complaints (device deficiencies-DD) is part of the BTIGER Study and should be 
done in addition to the AE/DD reporting requirements. It is the responsibility of the investigator to report 
all product complaints associated with a medical device distributed by Medtronic, regardless of whether 
they are related to intended use, misuse or abuse of the product. Reporting must be done immediately 
and via the regular channels for market-released products (Medical Device Reporting [21 CFR 803] in the 
US). 
Product Complaint: Any written, electronic or oral communication that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness or performance of a medical device that has 
been placed on the market. 
Reporting must be done immediately and via the regular channels for market-released products. The 
reporting of product complaints by the clinical team must be done according to the local Standard 
Operating Procedures. Medtronic will notify the regulatory authorities as applicable for the following 
incidents immediately upon learning of them and is not limited to AEs and DDs only: 
• 
Any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or instructions for use which led or might have 
led to the death or serious deterioration in the state of health of a patient, user, or other 
person. 

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• 
Any technical or medical reason resulting in withdrawal of a device from the market by 
the manufacturer. 
• 
Any serious deterioration in the state of health, including: 
 
Life-threatening illness or injury 
 
Permanent impairment of a body function or permanent damage to a body 
structure 
 
A condition necessitating medical or surgical intervention to prevent permanent 
impairment of a body function or permanent damage to a body structure 
12.5 Device Deficiency  
The DD definition is provided in Table 5. DD information will be collected throughout the study and 
reported to Medtronic. Note that DD that result in an AE to the subject should be captured as an AE only. 
13. Data Review Committees  
13.1 Clinical Events Committee Review 
This study will have the Steering Committee. The Steering Committee is composed of physicians with 
expertise in the area of Anesthesiology monitoring in pediatric patients, who will assume a leadership role 
in the overall study. The Steering Committee's roles are to:   
This study is considered a non-significant risk for study participants. Thus, the need for additional safety 
oversight beyond Medtronic’s already rigorous safety monitoring processes is not required. A Medtronic 
Medical Advisor, as needed, will provide an independent medical review according to the study Safety 
and Complaint Management Plan. The Medical Advisor will not be affiliated with an investigative center. 
14. Statistical Design and Methods 
Statistical analyses will be conducted by Medtronic or its designee as outlined in the Statistical Analysis 
Plan (SAP.) Any changes in statistical methods will be detailed in the Clinical Study Report. Data exclusion 
will be captured in the Data Management Plan.    
o 
Develop the protocol along with Medtronic, to ensure its scientific and statistical soundness;   
o 
Review the conduct of the study;  
o 
Help identify and resolve problems with recruitment or performance 

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14.1 General Aspects of Analysis 
Standard demographic information and baseline characteristics will be summarized using descriptive 
statistics. For safety assessments, adverse events (AEs) will be summarized using frequency counts and 
percentages. Descriptive statistics will be provided by severity and relationship as needed.  
 
The primary endpoint will be collected as a continuous variable every minute along with the BIS values. 
The primary analysis will be based on all evaluable data (excluding training subjects). Normality of data 
will be tested using the Kolmogorov-Smirnov test. Depending on whether normality assumption holds, a 
two-group t-test or Wilcoxon rank-sum test will be used to compare between the two treatment groups. 
A P-value of less than 0.05 is considered statistically significant unless otherwise specified. 
The training subjects will not be included in the analysis set for the primary and secondary endpoints. The 
training subjects will be summarized descriptively and separately. Any specific findings from these 
subjects will be noted and discussed in the study report. 
 
The following secondary endpoints will be evaluated: 
 
Time to first response (emergence) 
 
Time to PACU discharge readiness using Modified Aldrete Score 
 
Time to extubation 
 
Upon meeting the primary endpoint, the secondary endpoints will be evaluated using the Holm-
Bonferroni method. The method is a sequentially rejective multiple test procedure used to adjust 
multiplicity and to ensure the overall type I error rate is controlled at the 0.05 level. For statistical 
inferences, categorical variables will be evaluated using the Chi-square test or Fisher's exact test, and 
continuous variables will be evaluated using the t-test or Wilcoxon rank-sum test as appropriate.  The 
analysis details will be clearly specified in the Statistical Analysis Plan. 
Data Poolability  
The clinical study will be conducted under a common protocol for each investigational site with the 
intention of pooling the data for analysis. Every effort will be made to promote consistency in study 
execution at each study site. 
An assessment of data poolability of the sites will be performed using a mixed-effect model for the primary 
endpoint.  A significance level of 0.15 will be considered.  Sites with fewer than five subjects will be 
combined into large sites to ensure statistical robustness.  
If the sites are found to be significantly heterogeneous with respect to the primary endpoint, additional 
analyses will be conducted to further assess differences between sites in baseline and procedural 
variables that might contribute the differences.  

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Missing Data 
The primary analysis will include all evaluable data and missing values will not be imputed. BIS™ values 
that are outside of the specified range of 45 – 60 during maintenance of anesthesia for >35% of the 
maintenance duration will be considered a protocol deviation and will result in an exclusion of the subject 
from the primary analysis. The excluded subject will be replaced, and data from all excluded subjects will 
be noted and discussed in the final study report. Additionally, sensitivity analysis (e.g., multiple 
imputation) may be performed as appropriate to assess the robustness of study results.   
Additional Summaries and Considerations 
Cardiovascular variables will be summarized for both treatment groups. The incidence of hypotension will 
be summarized and compared to anesthesia sedation levels. 
 
The anesthetic requirements with the BIS™ value, the percentage of time during maintenance with BIS™ 
value within the specified ranges, and number of episodes and duration of burst suppression will be 
assessed for the BIS and SP groups.  
 
Additional endpoints, including the PAED scale, PACU discharge readiness and a subgroup analysis for 
subjects requiring neuromuscular blockade, will be evaluated by using descriptive statistics and compared 
between both groups.   
14.2 Sample Size Determination 
The first 2 - 4 subjects at each site will be enrolled to train the site team on the new technology and to 
determine the quality of data collection prior to randomization (n = 16-32). They will not be randomized 
and will not be included in the final analysis. For the analysis, a minimum of 36 subjects are required in 
each age group (18 per treatment group) for a minimum of 108 qualifying data sets. Subjects with non-
qualifying data sets will be rejected and replaced with a newly randomized subject. This sample size was 
independently powered for each of the 3 age groups based on data from a previously published study 
conducted by Emory University.[13] The sample size will provide more than 80% power to detect a 
difference of 0.5% in end-tidal sevoflurane concentration between the BIS™ and SP groups with a common 
standard deviation of 0.5% and two-sided significance level of 0.05.   
15. Ethics 
15.1. Statement(s) of Compliance  
The Investigator is responsible for ensuring that the clinical study is conducted in accordance with: 

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16. Study Administration 
16.1. Monitoring  
16.1.1 Monitoring Visits 
Site monitoring visits will be performed by the study monitor or other qualified sponsor staff per the 
monitoring plan to ensure: 
In-person or remote Monitoring Visits will be conducted at the start, during, and at the closure of the 
clinical study in accordance with Medtronic SOPs and the Monitoring Plan. An interim monitoring visit 
may be combined with the closing monitoring visit. Monitoring may be performed with in-person visits or 
remotely, when applicable. The quality of the device data obtained from the Investigator and maintained 
by the Sponsor will be confirmed through an internal review of data quality. Before any device data quality 
checks, the ICF will be checked in person or remotely. 
 
• 
This Clinical Investigational Plan and Standard Operating Procedures (SOPs). 
• 
Food and Drug Administration (FDA) Good Clinical Practice (GCP) guidelines and regulatory 
requirement(s), including 21 CFR 812.2, 21 CFR 50, 21 CFR 56. FDA Financial Disclosure regulations, as well 
as the International Conference on Harmonization (ICH) guidelines and any other regional/national 
requirements for clinical trials, as applicable.  
• 
If the IRB or other regulatory authority imposes any additional requirements (e.g., safety reports, progress 
reports, etc.), Medtronic will prepare the required documents and send them to the respective authority. 
• 
Investigators must inform Medtronic of any change in the status of IRB approval once the investigation 
site has started an enrollment. If any action is taken by an IRB with respect to the investigation, that 
information will be forwarded to Medtronic by the respective Investigator. 
• 
The clinical study will not begin until the IRB approval/ notification is received. Written IRB approval and 
any conditions of approval imposed by the IRB must be submitted to the Sponsor. 
• 
Overall compliance with the protocol, GCP, and the applicable regulations. 
• 
Accurate records are being maintained.  
• 
Accurate and complete study data are being reported (comparing CRF to source documents.) In some 
cases, the CRF will also be the source documentation of some information. 
• 
Informed consent has been obtained for all study subjects. 
• 
PI eligibility determination of each subject clearly documented. 
• 
Adverse events and protocol deviations are documented and reported. PI AE severity and relationship 
determination clearly documented.  
• 
Investigational and non-investigational device accountability and disposition are accurately 
documented.  

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The frequency of monitoring visits will occur based on subject enrollment, duration of the study, study 
compliance, site performance, site adherence to the protocol, findings from previous monitoring visits, 
and any suspected inconsistency in data that requires investigation. The monitoring visit frequency may 
be changed based on study needs and subject enrollment rates. Specific monitoring requirements are 
detailed in the study-specific Monitoring Plan. 
 
The Sponsor will provide updated contact lists, including the monitors’ name and contact information to 
the investigational sites.  
 
Medtronic or designee will conduct site monitoring visits to monitor compliance with the protocol, clinical 
study agreement, and applicable regulations, and adherence to the data collection procedures, to assess 
the accuracy and completeness of submitted clinical data, and to verify that records are being properly 
maintained for the duration of the study. 
 
Monitoring activities will be documented and include a summary of what the monitor reviewed and the 
observations regarding the completion of previous action items, significant findings, facts, deviations, 
conclusions, and recommended actions to be taken to secure compliance.  
 
If problems are encountered with the quality of the collected data, the study may be halted for the period 
of time until the problem has been assessed and corrected. The evaluation of the data quality will be the 
responsibility of the Medtronic Clinical Affairs personnel or designee.  
 
The Investigator or authorized study personnel should be available at each monitoring visit. Direct access 
to the subject records and other source data must be provided to study Monitor, the Sponsor, regulatory 
authorities, auditors, IRB members, or inspectors. 
 
Direct access to patient medical files for source data verification will need to be granted and prepared 
prior to any monitoring visits.  
 
Raw device data will not be monitored. 
16.2. Data Management 
The Investigator must ensure accuracy, completeness, and timeliness (goal of 7-10 days) of the data 
reported in the eCRFs and all other required reports. Data reported on the eCRFs which are derived from 
source documents must be consistent with the source documents, and discrepancies need to be justified 
in a documented rationale, signed and dated by the (principal) Investigator, and filed in the patient 
medical file. 

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Only authorized persons can complete eCRFs. All data requested on the eCRF are considered required. 
The Principal Investigator must ensure the accuracy and completeness of the recorded data and then 
provide his/her signature on the appropriate eCRFs. The Investigator’s electronic signature for specific 
eCRFs will be documented in compliance with local regulations. Changes to data previously submitted to 
the sponsor will require a new electronic signature by the Investigator to acknowledge/approve the 
changes. 
Medtronic will only consider eCRFs to be complete when all discrepancies have been resolved by the site 
and reviewed and closed by Medtronic. Also, specific eCRFs must be reviewed and electronically signed 
by the Investigator, indicating his/her agreement with the accuracy of all recorded data. It is expected 
that the Investigator and his/her staff will cooperate with the monitoring team and provide any missing 
data in a timely manner. 
The Electronic Data Capture (EDC) system maintains an audit trail on entries, changes, or corrections in 
eCRFs. Upon completion of an eCRF, the Investigator shall sign the eCRF in a timely manner, if a change 
to an already signed eCRF occurs, the Investigator shall re-sign this eCRF. 
16.3. Direct Access to Source Data/Documents  
The Principal Investigator(s), his/her delegate(s), and the study coordinator(s) shall be accessible to 
Medtronic field personnel and the Clinical Study Manager. This accessibility is of particular importance for 
reviewing data on the electronic Case Report Form (eCRF). Direct access to subject medical files for source 
data verification (if applicable) will need to be granted and prepared prior to any monitoring visits.  
Medtronic may conduct audits at participating study sites. The purpose of an audit is to verify the 
performance of the monitoring process and the study conduct, independently of the personnel directly 
involved in the study. RAs, such as the FDA, may also perform inspections at participating study sites. The 
investigator and/or institution shall permit Medtronic, IRBs and RAs direct access to source data and 
documents during monitoring, audits and regulatory inspections. 
Data entered must be traceable to source documents and cannot be directly recorded on the eCRF. Source 
documentation is defined as the first-time data appearance and may include original documents, data, 
and records (e.g., hospital records, clinical and office charts, procedure reports, laboratory records, or 
evaluation checklists, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, subject files.) 
 
The eCRFs (or paper copies) may not serve as source documents. Source documentation for data elements 
not routinely captured in medical records may vary from site to site; the site may use source document 
worksheets if identified as source documents and are signed and dated appropriately. 

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16.4. Confidentiality 
All records and other information about subjects participating in this study will be treated as confidential. 
The identity of a subject will never be disclosed in the event that study data are published.  
Subject confidentiality will be maintained throughout the clinical study in a way that ensures the 
information can always be traced back to the source data. For this purpose, a unique subject identification 
code will be assigned and used to allow identification of all data reported for each subject. 
Regulatory authorities and the IRB may also be granted direct access to the medical history records in 
order to comply with legal and regulatory requirements. Investigators are to instruct their staff in the 
methods and importance of maintaining subject confidentiality according to local and national regulations 
and institutional requirements. 
16.5. Liability 
Medtronic maintains appropriate clinical study liability insurance coverage as required under applicable 
laws and regulations and will comply with applicable local law and custom concerning specific insurance 
coverage. If required, a clinical study insurance statement/certificate will be provided to the IRB. 
16.6. CIP Amendments 
The Investigator may propose any appropriate modification(s) to the Clinical Investigation Plan. Medtronic 
will review and decide whether the modification(s) will be implemented. 
Medtronic will submit any amendment to the Clinical Investigation Plan, including a justification for such 
amendment, to the investigators to obtain approval from their IRB. 
Any amendment to the protocol requires written approval by the IRB and regulatory authority (if 
applicable) prior to its implementation unless there are overriding safety reasons. In some instances, an 
amendment may require a change to the ICF.  
The Sponsor and Investigator will obtain IRB approval concerning the revised ICF prior to the 
implementation of the change. The Investigator understands that subjects must be consented using the 
most current IRB approved version of the ICF. If the ICF is updated, subjects who have participated will be 
re-consented at the direction of the IRB. 
16.7. Record Retention 
Study-related documents including all study-related Source Documents, CRFs, ICFs, Investigator Site File 
(ISF), Final study reports, etc. should be maintained for a minimum of 2 years after the completion or 

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termination of the study or until the records are no longer required to support a marketing application 
(or longer in compliance to local requirements). The retention period may be longer if required by 
Medtronic or local or global regulatory requirements. Before the destruction of the study related data, 
the Investigator must notify the sponsor. The Principal Investigator will ensure that essential study 
documents are not destroyed until written permission has been obtained from Medtronic. 
An investigator may withdraw from the responsibility to maintain records for the period required, as 
indicated in the paragraph above, and transfer custody of the records to any other person who will accept 
responsibility. An investigator must notify the Sponsor prior records are being transferred.  
16.7.1 
Investigator Records 
The investigator is responsible for the preparation and retention of the records cited below. All of the 
below records, with the exception of case history records and case report forms, should be kept in the 
Investigator Site File (i.e., the study binder provided to the investigator) or Subject Study Binder. CRFs 
must be maintained and signed electronically within the electronic data capture system during the study. 
The following records are subject to inspection and must be retained for a period of two years (or longer 
as local law or hospital administration requires) after product approval or the date on which the 
investigation is terminated. 
• 
All correspondence between the IRB, sponsor, monitor, FDA, RA and the investigator that pertains 
to the investigation, including required reports.  
• 
Subject’s case history records, including:  
o Signed and dated IC.  
o Observations of AEs/ADEs/DDs 
o Medical history 
o Documentation of the dates and rationale for any deviation from the protocol 
• 
Randomization list  
• 
List of investigation study sites 
• 
FD  
• 
Subject screening log & ID log  
• 
Device Disposition Logs containing Model and serial numbers of devices delivered to the study 
site, received dates of devices, returned-to-sponsor dates and reasons, initials of all persons who 
received, used or disposed each device, and method of disposal/destruction.  
• 
All approved versions of the CIP, IC,  
• 
Signed and dated CTA.  
• 
CV of principal investigators and key members of investigation study site team (as required by 
applicable regulations. 
• 
Documentation of delegated tasks.  

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• 
IRB approval documentation. Written information that the investigator or other study staff, when 
member of the IRB, did not participate in the approval process. Approval documentation must 
include the IRBs composition, where required per local law.   
• 
RA notification, correspondence and approval, where required per local law. 
• 
Study training records for study site staff.  
• 
Any other records that FDA and local regulatory agencies require to be maintained.  
• 
Final Study Report including the statistical analysis.  
16.7.2 
Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation 
• 
Investigational device traceability record containing Model and serial numbers of devices, shipping 
date and name and address of person that received shipped device, location (if different than 
person shipped to), transfer and receipt by Medtronic dates.  
• 
Sample of label attached to investigational device 
• 
Signed Investigator Trial Agreements, FD (if applicable) and current signed CV of principal 
investigator and key members of the investigation study site team (as required by local law), 
delegated task list 
• 
All signed and dated case report forms submitted by investigator, including reports of AEs, ADEs 
and DDs (for non-OC studies) 
• 
All approved IC templates, and other information provided to the subjects and advertisements, 
including translations 
• 
Randomization records 
• 
Copies of all IRB approval letters and relevant IRB correspondence and IRB voting list/roster/letter 
of assurance 
• 
Names of the institutions in which the study will be conducted 
• 
RA correspondence, notification and approval as required by national legislation 
• 
Names/contact addresses of monitors 
• 
Monitoring visit reports 
• 
Statistical analyses and underlying supporting data 
• 
Final report of the study 
• 
The CIP and revisions 
• 
Study training records for study site personnel and Medtronic personnel involved in the study 
• 
Any other records that local regulatory agencies require to be maintained.  
 

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Medtronic records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in stored in secured file cabinets at 
Medtronic during the course of this study.  
After closure of the study Medtronic could archive records and reports indefinitely. 
16.8. Reporting Requirements 
16.8.1. 
Investigator Reports 
The investigator is responsible for the preparation (review and signature) and submission to the sponsor 
of all case report forms, adverse events and adverse device effects (reported per the country-specific 
collection requirements), device deficiencies, deaths, and any deviations from the clinical investigation 
plan.  If any action is taken by an IRB with respect to this study, copies of all pertinent documentation 
must be forwarded to Medtronic in a timely manner. Reports are subject to inspection and to the 
retention requirements as described above for investigator records.  
Safety data investigator reporting requirements are listed in Section 12. The investigator shall prepare and 
submit in a complete, accurate and timely manner the reports listed in this section. 
 
 
Table 8: Investigator reports applicable for all geographies per Medtronic requirements 
Report  
Submit to 
Description/Constraints 
Withdrawal of IRB 
approval 
Sponsor and Relevant 
Authorities 
The investigator must report a withdrawal of approval by the reviewing IRB 
of the investigator’s part of the investigation within 5 working days. 
Study Deviations  
Sponsor and 
IRB 
Any deviation from the clinical investigational plan shall be recorded 
together with the explanation of the deviation. 
Notice of deviations from the CIP to protect the life or physical well-being 
of a subject in an emergency shall be given as soon as possible, but no later 
than 5 working days after the emergency occurred.  Except in such 
emergency, prior approval is required for changes in the plan or deviations. 
Final Report 
IRBs and  
Relevant Authorities 
This report must be submitted within 3 months of study completion or 
termination. 
16.8.2. 
Sponsor Reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports listed in the 
tables below (by geography).  In addition to the reports listed below, Medtronic shall, upon request of the 
reviewing IRB, RA or FDA, provide accurate, complete and current information about any aspect of the 
investigation. Safety data Medtronic reporting requirements are listed in Section 12. 

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16.9. Publication and Use of Information 
The Medtronic Publication and Authorship Policy is aligned with the International Committee of Medical 
Journal Editors (ICMJE) recommendations (www.icmje.org). The Sponsor will seek to publish, in 
appropriate peer-reviewed journals and scientific conferences, results of clinical studies where human 
subjects are involved, regardless of the outcome. The study will be recorded on www.clinicaltrials.gov 
prior to the first enrollment. 
16.9.1. 
Publication Committee 
Medtronic may form the Publication Committee from study investigators. Medtronic personnel may serve 
as members of the committee. This committee will manage study publications with the goal of publishing 
findings from the data.  The Publication Committee will develop the final Publication Plan as a separate 
document.   
The Publication Committee’s role is to: 1) manage elements addressed in the publication plan as outlined 
in this appendix, 2) develop the final Publication Plan under separate cover, 3) execute the Publication 
Plan, 4) oversee the publication of primary and ancillary study results, 5) review and prioritize publication 
proposals, 6) provide input on publication content, and 7) determine authorship. In addition, the 
committee will apply and reinforce the authorship guidelines set forth in the Publication Plan.   
Membership in the Publication Committee does not guarantee authorship.  The committee will meet at 
regular intervals, as needed. 
16.9.2. 
Management of Primary, Secondary and Ancillary Publications 
The data may be published or used by study investigators provided that such publication or use is in 
accordance with this protocol, the Medtronic Publication and Authorship Policy, and the Clinical 
Investigation Agreement. The Publication Committee reviews, prioritizes, and manages all publications, 
including primary, secondary and ancillary publications. Primary and secondary publications are those 
that address analyses of any or all primary objectives or secondary objectives, respectively, as specified in 
the Clinical Investigation Plan.  
An ancillary publication is any publication that does not address the study objectives identified in the 
Clinical Investigation Plan. They include publications proposed and developed by other Medtronic 
departments or entities, clinicians participating in this clinical study, and clinicians not participating in this 
clinical study.   
The committee will work with Medtronic to ensure that requests do not present conflicts with other 
proposals, are not duplicative, and to determine which ancillary publication proposals, if any, will be 
supported.   

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The committee may decide that no publications, including abstracts, will be published prior to the end of 
the study or with individual site data.  Requests for publications on study objectives utilizing subset data 
(e.g., regional) will be evaluated for scientific validity and the ability of Medtronic to provide resources.   
Investigators must submit a copy of all manuscripts and/or abstracts to the Sponsor for review and 
comment 30 days prior to planned submission. Medtronic acknowledges that its right to review and 
comment shall relate solely to the proprietary, licensing, and/or confidential rights Medtronic may have 
in such proposed publication, rather than whether such results and/or opinions are favorable to 
Medtronic.   
16.9.3. 
Criteria for Determining Authorship 
Publications will adhere to authorship criteria defined by the International Committee of Medical Journal 
Editors (ICMJE, Uniform requirements for manuscripts submitted to biomedical journals, www.icmje.org).  
Individual authorship criteria defined by the target journal or conference will be followed when it differs 
from ICMJE criteria. 
Authors, including Medtronic personnel, must at a minimum meet all of the conditions below: 
• 
Substantial contributions to conception and design of the work, or the acquisition, analysis, or 
interpretation of data for the work; AND 
• 
Drafting the work or revising it critically for important intellectual content; AND 
• 
Final approval of the version to be published; AND 
• 
Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.  
 
Decisions regarding authorship and contributor-ship will be made by the committee. The selected authors 
will be responsible for drafting the publication. All selected authors must fulfill the authorship conditions 
stated above to be listed as authors, and all contributors who fulfill the conditions must be listed as 
authors. 
All investigators not listed as co-authors will be acknowledged as the “Medtronic <insert study name> 
Study Investigators” and will be individually listed according to the guidelines of the applicable scientific 
journal when possible and affiliation. Any other contributors will be acknowledged by name with their 
specific contribution indicated. 
16.9.4. 
Transparency 
Transparency of clinical study results will be maintained by the following means: 
• 
A final report, describing the results of all objectives and analysis, will be distributed to all 
investigators, ECs and CAs of participating countries when required by local law 

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• 
Registering and posting the study results on a <publicly accessible database, e.g., 
ClinicalTrials.gov> based on the posting rules stipulated  
• 
Submitting for publication the primary study results after the study ends  
• 
Disclosing conflicts of interest (e.g., financial) of the co-authors of publications according to the 
policies set forth by the corresponding journals and conferences  
• 
Making an individual study sites study data accessible to the corresponding investigator after the 
completion of the study, if requested 
16.10. Suspension or Early Termination 
The Sponsor reserves the right to discontinue the study at any stage, with written notice to all 
investigators and reviewing IRB. Similarly, investigators may withdraw from the study at any time, subject 
to providing written notification to the Sponsor 30 days prior to the date they intend to withdraw.  
 
The Sponsor and investigators will be bound by their obligation to complete the follow-up of subjects 
already participating in the study. If the study is terminated or suspended, no additional enrollment will 
be allowed unless otherwise informed by the sponsor. The current subjects will be followed according to 
the protocol, and information obtained during subject follow-up shall be reported to the Sponsor on the 
appropriate eCRF. 
 
If the study is terminated prematurely or suspended by the sponsor, the sponsor will promptly inform the 
investigators and regulatory authorities (if required) of the termination and the reason(s). The IRB will 
also be promptly informed and provided with the reason(s) for termination or suspension by the sponsor 
or by the Investigator. The Investigator will promptly inform the subjects and assure appropriate therapy 
and follow-up for the subject, as needed. 
 
If the Investigator (or IRB) terminates or suspends the investigation without the prior agreement of the 
sponsor, the Investigator will promptly inform the sponsor, the institution (if required), and the IRB and 
provide a detailed written explanation of the termination or suspension. The sponsor will inform the 
regulatory authorities (if required.) 
 
In the case of early termination of the study, all study subjects should be followed until the resolution of 
any pending adverse event(s.) 
 
Medtronic reserves the right to discontinue the study at any time for administrative or other reasons. 
Written notice of study termination will be submitted to the Investigator in advance of such termination. 
Possible reasons for considering study suspension or termination of the study for all centers include but 
are not limited to: 

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17. References 
1. 
Sikich, N. and J. Lerman, Development and psychometric evaluation of the pediatric anesthesia 
emergence delirium scale. Anesthesiology, 2004. 100(5): p. 1138-45. 
3. 
Knapp, R.M., A Deeper Look at Anesthesia Depth. Anesthesiology, 2017. 127(5): p. 904-905. 
4. 
Rampil, I.J., A Primer for EEG Signal Processing in Anesthesia. Anesthesiology, 1998. 98(4): p. 
980-1002. 
5. 
Akeju, O., et al., Effects of Sevoflurane and Propofol on Frontal Electroencephalogram Power and 
Coherence. Anesthesiology, 2014. 121(5): p. 990-998. 
6. 
Clark, D.L. and B.S. Rosner, Neurophysiologic effects of general anesthetics. I. The 
electroencephalogram and sensory evoked responses in man. Anesthesiology, 1973. 36(6): p. 
564-582. 
7. 
Gan, T.J., P.S. Glass, and A. Windsor, Bispectral index monitoring allows faster emergence and 
improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study 
Group. Anesthesiology, 1997. 87(4): p. 808-815. 
8. 
Davidson, A.J., et al., The differences in the bispectral index between infants and children during 
emergence from anesthesia after circumcision surgery. Anesth Analg, 2001. 93(2): p. 326-30, 2nd 
contents page. 
9. 
Degoute, C.S., et al., EEG bispectral index and hypnotic component of anaesthesia induced by 
sevoflurane: comparison between children and adults. Br J Anaesth, 2001. 86(2): p. 209-12. 
10. 
Denman, W.T., et al., Pediatric evaluation of the bispectral index (BIS) monitor and correlation of 
BIS with end-tidal sevoflurane concentration in infants and children. Anesth Analg, 2000. 90(4): 
p. 872-7. 
11. 
Tschiedel, E., et al., Sedation monitoring during open muscle biopsy in children by Comfort Score 
and Bispectral Index - a prospective analysis. Paediatr Anaesth, 2015. 25(3): p. 265-71. 
12. 
Frederick, H.J., et al., A Randomized Controlled Trial to Determine the Effect of Depth of 
Anesthesia on Emergence Agitation in Children. Anesth Analg, 2016. 122(4): p. 1141-6. 
13. 
Bannister, C.F., et al., The effect of bispectral index monitoring on anesthetic use and recovery in 
children anesthetized with sevoflurane in nitrous oxide. Anesth Analg, 2001. 92(4): p. 877-81. 
• 
Failure to obtain initial IRB approval or annual renewal of the study; 
• 
Consistent non-compliance to the CIP (e.g., failure to adhere to inclusion/exclusion criteria, failure to 
follow subjects per scheduled follow-ups, failure to implement required corrective and preventive actions, 
etc.); 
• 
Lack of enrollment; 
• 
Non-compliance to regulations and the terms of the Clinical Trial Agreement (e.g., failure to submit data in 
a timely manner, failure to follow-up on data queries and monitoring findings in a timely manner, etc.); 
• 
IRB suspension of the center; 
• 
Fraud or fraudulent misconduct (as defined by local law and regulations); 
• 
Investigator request (e.g., no longer able to support the study). 

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14. 
Akeju, O., et al., Age-dependency of sevoflurane-induced electroencephalogram dynamics in 
children. Br J Anaesth, 2015. 115 Suppl 1: p. i66-i76. 
15. 
Aldrete, J.A. and D. Kroulik, A Postanesthetic Recovery Score. Anesth Analg, 1970. 49(6): p. 924. 
16. 
Aldrete, J.A., The post-anesthesia recovery score revisited. Journal of Clinical Anesthesia, 1995. 
7(1): p. 89-91. 
17. 
Rice-Townsend, S., et al., Analysis of adverse events in pediatric surgery using criteria validated 
from the adult population: justifying the need for pediatric-focused outcome measures. J Pediatr 
Surg, 2010. 45(6): p. 1126-36. 
18. 
Kakavouli, A., et al., Intraoperative reported adverse events in children. Paediatr Anaesth, 2009. 
19(8): p. 732-9. 
18. Appendices  
Appendix A – Pediatric Anesthesia Emergence Delirium (PAED) [1] 
The PAED Scale 
 
Item scores are added together for a total score, with higher scores indicating more severe delirium 
Items 1,2,3 are scored as follow: 
4 = not at all 
3 = just a little  
2 = quite a bit  
1 = very much 
0 = extremely 
Items 4 and 5 are scored as followed   
0 = not at all 
1 = just a little  
2= quite a bit 
3 = very much 
4 = extremely 
Items 
Sore 
Total Score  
 
 
 
 
 
 
1. Child makes eye contact with caregiver 
 
2. Child’s actions are purposeful 
 
3. Child is aware of his/her surroundings 
 
4. Child is restless 
 
5. Child is inconsolable 
 

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Appendix B – Wong-Baker FACES Scale [2, 3] 
 
Date of Assessment: _________________     Time of Assessment: _______________ 
 
Appendix C – Modified Aldrete Scoring System [15, 16]  
 

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19. Version History 
 
Version 
Summary of changes 
Author(s)/Title 
1.0 
• 
Not Applicable, New Document 
Julia Katilius, Ph.D./ Sr. Clinical Program Manager 
Stephanie Monza/Sr. Clinical Research Specialist 
2.0 
• 
Revision to new Operating Unit 
• 
Correction to Wong-Baker Collection criteria 
Stephanie Monza, Sr. Clinical Research Specialist 
3.0 
1. Changes to title page to remove unused 
rows 
2. Addition of signal quality index (SQI) to 
glossary 
3. Change definition of time of surgical 
procedure to maintenance duration to align 
with statistical analysis plan 
4. Increase number of sites up to eight 
5. Addition of pre-operative vitals obtained in 
pre-operative holding to 
baseline/enrollment visit procedures and 
assessments 
6. Change of surgeries approved for study to 
allow for approval of additional surgery 
types by study team 
7. Change in allowed % of time outside of BIS 
range for BIS-guided subjects from 25% of 
35% to improve number of qualifying cases 
(business decision) 
8. Change in Wong-Baker FACES Pain Rating 
Scale to be performed only when subject is 
awake to avoid unnecessary protocol 
deviations 
9. Completion of recovery assessments 
changes from every 5 minutes to every 15 
minutes 
10. Addition of required variables to list of 
timepoints for BIS, ETSevo, FiO2, and EtO2 
data collection needed for outcome analysis 
11. Clarification of procedure and recovery 
variables 
Ami Stuart, Ph.D., Sr. Clinical Research Specialist 

Bispectral Index and End Tidal Anesthetic Gas Concentration in Pediatric 
Patients undergoing Sevoflurane Anesthesia Clinical Investigation Plan  
 
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12. Update of missing references throughout 
document 
13. Update to data collection table 5 to include 
emergence and adverse event assessment in 
PACU if applicable 
14. Removal of confusing language in 10.7 
Baseline around what is recorded where. All 
data should be recorded in source and CRF 
per section 16.2 and Case Report Form 
Completion Guidelines.  
15. Clarity around Adverse Event language 
16. Update to Clinical Affairs Clinical Study 
Manager (CSM) contact from Stephanie 
Monza to Ami Stuart as Stephanie Monza is 
no longer the CSM or Safety Manager 
17. Minor grammar/spelling revisions 
18. Update to 056-F275, v D Clinical 
Investigational Plan Template 
4.0 
1. Sample size section in summary and 14.2 
updated to reflect the required number of 
cases to be analyzed.  
2. Minor grammar/spelling revisions 
Ami Stuart, Ph.D., Sr. Clinical Research Specialist 
4.1 
1. Update to current template 
Ami Stuart, Ph.D., Sr. Clinical Research Specialist