Evaluation of BIS™ and Levels of Sedation With Common Inhalational Anesthetics in Healthy Volunteers (OLIVER)
Phase: NA
Conditions: Anesthesia
Sponsor: Medtronic - MITG

Evaluation of BIS™ and Levels of Sedation with Common Inhalation Anesthetics 
in Healthy Volunteers  
Clinical Investigation Plan  
 
MDT19053OLIVER 
Version 5.0 
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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  
Evaluation of BIS™ and Levels of Sedation with 
Common Inhalational Anesthetics in Healthy 
Volunteers (OLIVER)  
Clinical Investigation Plan Identifier MDT19053OLIVER 
Study Product Name BIS™ Complete Monitoring System 
Sponsor/Local Sponsor 
Medtronic,  
Medical Surgical Portfolio 
Patient Monitoring OU  
6135 Gunbarrel Avenue, 
Boulder, CO 80301 
U.S.A. 
Document Version 5.0 
Version Date 06JAN2022 
Lead Principal Investigator 
David MacLeod, M.B.B.S 
Duke University Hospital 
2301 Erwin Road 
Durham, NC 
27710, USA 
Coordinating Investigator 
Talmage Egan, MD 
University Hospital 
50 North Medical Drive 
Salt Lake City, UT 84132 
 
Odmara Barreto Chang, MD, PhD 
University of California, San Francisco 
513 Parnassus Ave 
San Francisco, CA 94143 
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. 
 
 

Evaluation of BIS™ and Levels of Sedation with Common Inhalation Anesthetics 
in Healthy Volunteers  
Clinical Investigation Plan  
 
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Table of Contents  
 
Table of Contents ...................................................................................................................... 2 
Table of Tables .......................................................................................................................... 5 
Table of Figures ......................................................................................................................... 6 
2. 
Glossary .............................................................................................................................. 6 
3. 
Synopsis ............................................................................................................................. 9 
4. 
Introduction ..................................................................................................................... 19 
4.1. Background ........................................................................................................................... 19 
Basics of Anesthesia & Anesthetics .................................................................................................... 19 
EEG Monitoring in Anesthesia ............................................................................................................ 20 
Clinical Summary ................................................................................................................................. 21 
Purpose ........................................................................................................................................ 21 
5. 
Objectives ........................................................................................................................ 22 
5.1. Objectives ............................................................................................................................. 22 
Primary Objective(s) ............................................................................................................................ 22 
Secondary Objective(s) ....................................................................................................................... 22 
6. 
Study Design .................................................................................................................... 22 
6.1. Duration ................................................................................................................................ 23 
6.2. Rationale ............................................................................................................................... 24 
7. 
Product Description.......................................................................................................... 25 
7.1. General ................................................................................................................................. 25 
7.2. Manufacturer ......................................................................................................................... 25 
7.3. Packaging .............................................................................................................................. 25 
7.4. Intended Population ............................................................................................................... 25 
BIS™ Complete Monitoring System Indications for Use ..................................................................... 26 
7.5. Equipment ............................................................................................................................. 26 
BIS™ Complete Monitoring System .................................................................................................... 26 
BISx4™ ................................................................................................................................................. 27 

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Patient Interface Cable ....................................................................................................................... 27 
BIS™ Bilateral Sensor .......................................................................................................................... 28 
Other Equipment ................................................................................................................................ 28 
Site’s Equipment/Supplies .................................................................................................................. 28 
7.6. Product Use ........................................................................................................................... 28 
7.7. Product Training Requirements ............................................................................................... 29 
7.8. Product Receipt and Tracking ................................................................................................. 29 
7.9. Product Storage ..................................................................................................................... 29 
Product Return .............................................................................................................................. 29 
Product Accountability ................................................................................................................... 29 
8. 
Study Site Requirements ................................................................................................. 30 
8.1 Investigator / Investigation Study Site Selection ...................................................................... 30 
8.2 Study Site Activation .............................................................................................................. 30 
8.3 Role of the Sponsor Representatives ....................................................................................... 31 
9. 
Selection of Subjects ........................................................................................................ 31 
9.1. Study Population .................................................................................................................... 31 
9.2. Subject Enrollment ................................................................................................................. 31 
9.3. Inclusion Criteria .................................................................................................................... 31 
9.4. Exclusion Criteria ................................................................................................................... 32 
10. 
Study Procedures........................................................................................................... 33 
10.1. 
Schedule of Events ........................................................................................................... 33 
10.2. 
Subject Pre-Screening/Screening ....................................................................................... 34 
10.3. 
Subject Consent ............................................................................................................... 34 
10.4. 
Enrollment - Visit 1 ........................................................................................................... 35 
10.5. 
Execution - Visit 2 ............................................................................................................ 36 
Pre-Procedure ..................................................................................................................................... 36 
Randomization .................................................................................................................................... 36 
Procedure ............................................................................................................................................ 37 
10.6. 
Follow-up ......................................................................................................................... 42 
Phone Call ........................................................................................................................................... 42 
10.7. 
Assessment of Efficacy ..................................................................................................... 42 

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10.8. 
Assessment of Safety ....................................................................................................... 42 
10.9. 
Recording Data ................................................................................................................ 43 
10.10. 
Deviation Handling ........................................................................................................... 43 
10.11. 
Subject Exit, Withdrawal or Discontinuation ....................................................................... 44 
11. 
Risks and Benefits ......................................................................................................... 45 
11.1. 
Potential Risks .................................................................................................................. 45 
11.2. 
BIS™ Sensor Risks ........................................................................................................... 45 
11.3. 
BIS™ Monitoring System Risks .......................................................................................... 46 
11.4. 
XAVANT STIMPOD™ Quantitative NMT Monitor .................................................................. 48 
11.5. 
Nellcor™ Pulse Oximeter ................................................................................................... 49 
11.6. 
General Anesthesia Risks .................................................................................................. 50 
11.7. 
Potential Benefits ............................................................................................................. 54 
11.8. 
Risk-Benefit Rationale ....................................................................................................... 54 
12. 
Adverse Events and Device Deficiencies ....................................................................... 55 
12.1. 
Adverse Events ................................................................................................................ 55 
12.2. 
Device Deficiency ............................................................................................................. 55 
12.3. 
Processing Updates and Resolution ................................................................................... 56 
12.4. 
Definitions/Classifications .................................................................................................. 56 
12.5 Reporting of Adverse Events ................................................................................................... 57 
12.5.1 Adverse Event and Device Deficiency Classification ................................................................ 57 
12.5.2 Adverse Event and Device Deficiency Reporting Requirements ............................................. 58 
12.6 Product Complaint Reporting .................................................................................................. 60 
13. 
Data Review Committees .............................................................................................. 60 
14. 
Statistical Design and Methods ..................................................................................... 61 
14.1. 
Sample Size Justification ................................................................................................... 61 
14.2. 
Analysis Populations ......................................................................................................... 61 
14.3. 
Statistical Methods ........................................................................................................... 61 
14.4. 
Interim Review ................................................................................................................. 62 
15. 
Ethics ............................................................................................................................. 62 
15.1. 
Statement(s) of Compliance .............................................................................................. 62 
16. 
Study Administration ..................................................................................................... 63 

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16.1. 
Monitoring ....................................................................................................................... 63 
16.2. 
Data Management ............................................................................................................ 64 
16.3. 
Direct Access to Source Data/Documents ........................................................................... 64 
16.4. 
Confidentiality .................................................................................................................. 65 
16.5. 
Liability ............................................................................................................................ 65 
16.6. 
CIP Amendments ............................................................................................................. 65 
16.7. 
Record Retention ............................................................................................................. 65 
16.7.1 
Investigator Records .......................................................................................................... 65 
16.7.2 
Sponsor Records ................................................................................................................ 67 
16.8. 
Reporting Requirements ................................................................................................... 67 
Investigator Reports ............................................................................................................................ 67 
Sponsor Reports .................................................................................................................................. 68 
16.9. 
Publication and Use of Information .................................................................................... 68 
16.10. 
Suspension or Early Termination ....................................................................................... 69 
17. 
References ..................................................................................................................... 70 
18. 
Appendices .................................................................................................................... 73 
Appendix A - Modified Observer's Assessment of Alertness/Sedation scale ........................................ 73 
19. 
Version History .............................................................................................................. 78 
 
Table of Tables  
Table 1: Clinical Data from Literature .......................................................................................................................... 21 
Table 2: System product/component information for the United States ................................................................... 33 
Table 3: Schedule of Events ......................................................................................................................................... 32 
Table 4: Possible Side Effects using Medication .......................................................................................................... 49 
Table 5: Adverse Event and Device Deficiency Definitions .......................................................................................... 53 
Table 6: Adverse Event Classification Responsibilities ................................................................................................ 55 
Table 7: Reporting Requirements ................................................................................................................................ 56 
Table 8: Investigator reports applicable for all geographies per Medtronic requirements ........................................ 65 
 

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Table of Figures 
Figure 1: BIS™ Range Guidelines; a general association between clinical state and BIS™ values ............................... 21 
Figure 2: The BIS™ Complete Monitoring System. 1 - Monitor Interface Cable; 2 - BIS™ Monitor; 3- BIS™ bilateral 
sensor will be used; 4- Patient Interface Cable (PIC); 5- BISx4™ (LoC 4 Channel) ....................................................... 27 
Figure 3: BISx4™ and PIC.  1- Monitor Interface Cable; 2- Patient Interface Cable; 3- BISx4™ (BIS LoC 4 Channel) ... 27 
Figure 4: BIS™ Bilateral Sensor .................................................................................................................................... 28 
 
 
2. Glossary 
Term 
Definition/Acronyms 
ADE 
Adverse Device Effect 
AE 
Adverse Event  
AEAC 
Adverse Events Advisory Committee 
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  
BMI 
Body Mass Index 
bpm 
Beats per minute 
CA 
Competent Authority 
CBC 
Complete Blood Count 
CIP 
Clinical Investigational Plan 
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. Forms where the clinical data are collected. eCRF is the electronic version of the 
CRF 
CTA 
Clinical Trial Agreement 
CV 
Curriculum Vitae 
DD 
Device Deviation 

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Term 
Definition/Acronyms 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
EC 
Ethics Committee 
ECG 
Electrocardiogram. A diagnostic tool that measures and records the electrical activity of the heart 
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 
EMR 
Electronic Medical Record. Digital version of a patient’s medical record within a single facility. 
ET 
End-tidal concentration 
ETDES 
End-tidal concentration of Desflurane 
ETSEVO 
End-tidal concentration of Sevoflurane 
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 
Hz 
Hertz 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
IV 
Intravenous 
IPPV 
Intermittent positive pressure ventilation  
IRB 
Institutional Review Board 
ISF 
Investigator Site File. Regulatory binder supplied by the sponsor 

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Term 
Definition/Acronyms 
LMA 
Laryngeal mask 
LOC 
Level of consciousness 
MAC 
Minimum alveolar concentration 
MOAA/S 
Modified Observer's Assessment of Alertness/Sedation 
NSR 
Non-significant Rsik 
PI 
Principal Investigator. The person responsible for overseeing the study and assuring study 
completion in compliance with applicable regulations. 
PIC 
Patient Interface Cable 
PK/PD 
Pharmacokinetics and pharmacodynamics 
POC 
Point of Care 
RA 
Regulatory Authority 
SpO2 
A non-invasive spectroscopic estimate of arterial oxygen saturation measured transcutaneously by 
a pulse oximeter 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedures 
TES 
Tetanic Electrical Stimulation 
TCI 
Target-controlled infusion 
TIVA 
Total Intravenous Anesthesia 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 

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3. Synopsis 
Title 
Evaluation of BIS™ and Levels of Sedation with Common Inhalational 
Anesthetics in Healthy Volunteers (OLIVER)  
Product Name 
Bispectral Index Sensor (BIS™) Complete Monitoring System  
Sponsor  
Medtronic  
Medical Surgical Portfolio 
Patient Monitoring OU 
6135 Gunbarrel Avenue 
Boulder, CO 80301  
Indication under 
investigation 
Validation of the BIS™ index, one of the Complete Monitor output parameters, 
as an aid in monitoring the effects of desflurane, isoflurane and sevoflurane 
with balanced anesthetic techniques for adult patients.  
Investigation 
Purpose 
To investigate the relationship between BIS™ and inhaled anesthetics across a 
wide range of anesthetic concentration and hypnotic states, and to provide 
evidence to support BIS™ performance in use with isoflurane, sevoflurane and 
desflurane in combination with opioids. 
Product Status  
BIS™ is commercially available in the United States 
Primary Objective 
To determine BIS50 (BIS™ value at which 50% of patients will be unresponsive at 
a given drug concentration)  
Secondary 
Objective(s) 
To determine BIS95 (BIS™ value at which 95% of patients will be unresponsive at 
a given drug concentration)  
To determine Prediction Probability (PK) for correctly predicting if the subject 
was responsive or unresponsive.  
Study Design 
This is a prospective, randomized study to collect data to evaluate the 
relationship between BIS™ and inhaled anesthetics without and with opioids. 
Five groups of anesthetics regimens will be studied as follow:  
1. Sevoflurane alone  
2. Sevoflurane with Remifentanil  
3. Sevoflurane with Fentanyl  
4. Desflurane alone  
5. Isoflurane alone 

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Healthy Volunteer Subjects will be randomized to one of the anesthetic 
regimen groups. The BIS™ bilateral sensor will be placed on the subject’s 
forehead to study the effects of these drugs on the brain. Each subject will be 
given a sequence of dose ranges of the target drug to achieve targeted drug 
concentration.  
If required, a training group, comprising of the first 2 - 4 subjects at each site 
will be enrolled to train the site team on the technology and to determine the 
quality of data collection, as required, prior to randomization. Afterward, 
randomization will proceed based on the Sponsor’s assessment of data quality.  
The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale will 
be used at each steady-state step to measure the level of alertness in sedated 
subjects. Subjects will then be assessed using a Picture Recall assessment with a 
standardized set of pictures. Tetanic Electrical Stimulation (TES) will be used 
once the patient is unresponsive to painful stimuli (e.g., MOAA/S = 0, BIS™ < 
40).   
TES will then be initiated once the subject reaches a MOAA/S = 0, BIS™ value < 
40 at the highest concentration of anesthesia anticipated, with an increasing 
stimulation starting at 20mA, 50 Hz delivered for 1-5 seconds. If the subject 
does not purposefully (i.e. attempting to push the stimulus away) respond, the 
stimulation will increase to 30mA, 50Hz for 1-5 seconds, then 40mA, 50 hertz 
(Hz) for 1-5 seconds and finally to 50mA, 50Hz for 1-5 seconds. If there is still no 
purposeful response, the subject will be considered a non-purposeful 
responder (i.e. exhibiting a reflex withdrawal, facial grimace, or groan) and their 
response such as withdrawal of extremity, facial grimace or other will be 
recorded along with the BIS™ value prior to stimulation, at the end of all 
stimulation and approximately 2 minutes later, to allow for equilibration, 
following stimulation. If the subject does respond to any of the stimulations 
with a purposeful response, the TES will be ended, the response will be noted 
and the BIS™ value will be recorded at the time TES is ended and at 
approximately 2 minutes following the stimulation. Anesthesia will then be 
decreased in the same steps until subject is conscious.  
Randomization 
Once enrolled, subjects will be equally randomized to one of the anesthetic 
regimen groups. 
Sample Size 
A two-stage adaptive design is used in this study. For each regimen group, 10 
subjects will be enrolled in stage 1, and upon evaluation, up to 20 additional 
subjects will be enrolled in stage 2. With 5 regimen groups, a maximum of 150 
subjects will be enrolled. Based on the dose-response equation (logistic model) 
with an allowable error of ± 15% for BIS50 and a coefficient of variation of 25% 
at the alpha level of 0.05, the sample size will provide sufficient power (>80%) 
to evaluate the performance of anesthetic agents.   

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Duration  
Study duration is expected to be up to approximately 9 months. The expected 
duration of each subject’s participation is approximately 6 hours for both 
enrollment and procedure. The Enrollment Visit should take approximately 2 
hours to complete, and the Study Visit will be approximately 4 hours per 
subject. Each subject will be contacted by phone within 48 hours of the study 
participation.   
Planned number of 
sites 
Three to four investigational sites in the US 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria: 
1) Healthy (American Society of Anesthesiology (ASA) physical status 1), 
male or female subjects between the ages of 18 to 60 years; 
2) Completion of a health screening for a medical history by a licensed 
physician, nurse practitioner or physician assistant;  
3) Vital signs must be within the following ranges to be included: Vital 
signs measured sitting after 3 minutes rest; heart rate: 45-90 beats per 
minute (bpm); systolic blood pressure: 110-140; diastolic blood 
pressure: 50-90. Out-of-range vital signs may be repeated once. [Pre-
dose vital signs will be assessed by the Principal Investigator or 
designee (e.g., a medically qualified sub-investigator) before study drug 
administration. The Principal Investigator (PI) or designee will verify the 
eligibility of each subject with out-of-range vital signs and document 
approval before dosing].  
Exclusion Criteria:  
1) Has severe contact allergies that may cause a reaction to standard 
adhesive materials found in pulse oximetry sensors, electrocardiogram 
(ECG) electrodes, respiration monitor electrodes, or other medical 
sensors [self-reported];  
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) [self-reported and assessment by PI or delegate]; 
3) Known cardiovascular disease (e.g., hypertension, coronary artery 
disease, prior acute myocardial infarction, any valvular and/or 
myocardial disease involving a decrease in ejection fraction, 
arrhythmias, which are either symptomatic or require continuous 
medication/ pacemaker/ automatic internal cardioverter defibrillator), 
current implanted pacemaker or automatic internal cardioverter 
defibrillator [self-reported and assessment by PI or delegate]; 

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4) Has a clinically significant abnormal finding on medical history, physical 
examination, clinical laboratory tests, or ECG at the screening [self-
reported and assessment by PI or delegate]; 
5) Use of psychoactive medication within the past 60 days (e.g., 
benzodiazepines, antiepileptic drugs, Parkinson’s medication, anti-
depressant drugs, opioids) [self-reported and assessment by PI or 
delegate]; 
6) Subjects with known gastric diseases [self-reported and assessment by 
PI or delegate]; 
7) Has a positive urine cotinine test or urine drug screen or oral ethanol 
test [point of care (POC) testing]; 
8) Known history of allergic or adverse response to drugs to be 
administered [self-reported];  
9) Known history of complications relating to previous general anesthesia 
or conscious sedation [self-reported and assessment by PI or delegate]; 
10) Known history of malignant hyperthermia [self-reported and assessment 
by PI or delegate]; 
11) Has a room air saturation less than 95% by pulse oximetry [measurement 
by PI or delegate]; 
12) Has a clinically significant abnormal pulmonary function test via 
spirometry [assessment by PI or delegate]; 
13) Pregnant or lactating women [assessed by urine test and self-reported]; 
14) Subjects with tattooed skin specific to the sensor placement areas 
(forehead, fingers, chest) [self-reported and assessment by PI or 
delegate]; 
15) The subject must not take any prescription medication, except female 
hormonal contraceptives or hormone replacement therapy, from 14 
days before the dosing until the end-of-study visit without evaluation 
and approval by the Investigator. Subjects who participated in a 
previous clinical trial who received a required Food and Drug 
Administration (FDA) approved concomitant medication, for example, 
naltrexone, but were not randomized may be considered for 
participation in this study if they meet the washout requirement 
[assessment by PI or delegate]. 
Study Procedures 
and Assessments 
Pre-Screening: 
• 
Online or phone call pre-screening 
Enrollment Visit (Visit 1): 
• 
Informed Consent Process 
• 
Medical Screening: 

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o Medical History 
o Physical Examination 
o ASA physical assessment 
o Electrocardiogram (ECG) 
o Complete Blood Count (CBC) 
o Urine Testing for presence of: 
o Cotinine (nicotine metabolite) 
o Pregnancy- for subjects able to bear children 
 
The subject will be instructed not to consume beverages and foods containing 
alcohol, grapefruit, or caffeine/xanthine from 48 hours before dosing until the 
end-of-study visit. All subjects will fast as it will be instructed by the 
Investigator or designee before the start of the drug administration. The per 
dosing instructions will be provided to the subject.  
Study enrollment is accomplished by signing of the informed consent and 
successfully passing the study inclusion/exclusion criteria and health screening 
evaluation. Subjects who sign informed consent, but are not enrolled, are 
considered screen failures. 
Execution Visit (Visit 2): 
Prior to Randomization: 
• 
Inclusion/Exclusion Assessment 
• 
Vital Signs 
• 
Urine Testing for presence of: 
• 
Cotinine (nicotine metabolite) 
• 
Pregnancy- for subjects of childbearing potential 
• 
Alcohol Breathalyzer 
 
Randomization 
Procedure: 
• 
BIS™ sensor application and connection to BIS™ Monitor 
• 
TES sensor application to the calf with a stimulation of 5mA, 5Hz for 1-5 
seconds or per device Instructions for Use (IFU) provided to ensure 
proper application 
• 
Safety Management 
• 
Intravenous Catheter Insertion for fluid and drug administration 
• 
Blood pressure monitoring 
• 
Electroencephalogram (EEG), Pulse Oximeter for saturation pulse oxygen 
(SpO2), Capnography (or another system) for respiratory rate, and end-
tidal carbon dioxide (EtCO2) 

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• 
BIS™, Picture Recall Test (for the sevoflurane, sevoflurane with 
remifentanil and sevoflurane with fentanyl groups), Modified Observer's 
Assessment of Alertness/Sedation (MOAA/S) Assessments 
TES assessment as described above. A clinician will be monitoring respiratory and 
cardiac functions to determine if interventions are needed to maintain an 
adequate airway. The respiration support will be provided to ensure an 
unobstructed airway, adequate oxygenation (SpO2 > 92%), and carbon dioxide 
(CO2) homeostasis throughout the study. As needed for airway support, the 
anesthesiologist may gently lift chin or jaw thrust (with or without manually 
assisted breathing), insertion of an airway device (oropharyngeal airway or 
laryngeal mask airway) and/or intermittent positive pressure ventilation (IPPV). 
Mask or nasal cannula will be used for supplemental oxygen (O2) delivery. Any 
study procedures may be discontinued for the subject’s safety.  
The opioids (remifentanil and fentanyl) will be administered via the target-
controlled infusion (TCI) pump using either the preprogrammed pump 
protocols or computer-controlled program, e.g., Total Intravenous Anesthesia 
(TIVA) Trainer, or another computer-controlled program, to ensure that the 
targeted effect-site concentration of a drug is reached and maintained at each 
drug concentration plateau. Remifentanil and Fentanyl diluted to a single 
concentration of 50 µg/ml will be used for this study. The infusion rate between 
0 and 1200 ml/hr will be used to achieve a target effect-site concentration of 
remifentanil and fentanyl. For remifentanil, Minto 
pharmacokinetics/pharmacodynamics (PK/PD) model will be used. [1] The 
kinetic model for fentanyl will not be weight-adjusted.[2]  
Inhalation anesthetic drugs will be administered via a tight-fitting face mask or 
a laryngeal mask (LMA). Volunteers will be connected to a circular breathing 
system of an anesthesia machine. After the volunteer loses responsiveness, 
LMA may be inserted as needed to facilitate airway control at deeper levels of 
anesthesia. Once emergence is started, LMA should be removed at the earliest 
point while ensuring subject safety. Inhalation agents will be administered with 
O2 to maintain saturation of greater than 90%. 
Lidocaine can be administered per Investigator discretion as a bolus over 3-5 
seconds at a maximum concentration of 100mg to aid in the infusion of 
propofol for subject’s comfort. 
Phenylephrine may be used prophylactically on all subjects at a concentration 
of 100 mcg/mL for the prevention of hypotension as a result of inhaled 
anesthetics. 
Antiemetic / anti-nausea medication (i.e. Ondansetron) may be used 
prophylactically on all subjects for the prevention of nausea and vomiting at the 
investigator’s discretion.  

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Each subject will receive one of the anesthetic groups. The subject will rest for 
at least 12 minutes before starting any regimen.  
Sevoflurane Group, following approximately 2 minutes of baseline 
measurement, sevoflurane will be administered via a tight-face mask in steps to 
achieve a loss of consciousness by increasing the end-tidal concentration of 
sevoflurane (ETSEVO). Targeted concentration for ETSEVO are 0.2, 0.5, 0.7, 1, 2, 3, 
4, 5% or higher until a BIS™ value not less than 30 is reached or per 
Investigator’s discretion. The BIS™ value should be taken to at least 40, but not 
intentionally below 30.  The equilibration time for each targeted concentration 
will be approximately 12 minutes to maintain a constant ETSEVO. The BIS™ value, 
MOAA/S score and Picture Recall test will be assessed when the patient is 
awake and prior to the induction of any anesthetic and at each ETSEVO 
concentrations. TES will then be initiated once the subject reaches a MOAA/S = 
0, BIS™ value < 40 at the highest concentration of anesthesia anticipated. The 
BIS™ value will be recorded at the immediate end of the assessment and 
approximately 2 minutes following the TES assessment.   
ETSEVO is decreased by the same steps until consciousness is regained.  
Sevoflurane with Remifentanil Group, approximately 2 minutes prior to 
starting sevoflurane, to attain an effect-site targeted concentration of 
remifentanil of 4 ng/ml, an initial IV bolus of remifentanil will be given followed 
by the start of an infusion. Approximately within 7 minutes, the infusion rate of 
remifentanil may be adjusted to maintain the effect-site concentration of 
remifentanil of 4 ng/ml.  
Sevoflurane will be administered via a tight-face mask in steps to achieve a loss 
of consciousness by increasing the end-tidal concentration of sevoflurane 
(ETSEVO). Targeted concentration for ETSEVO are 0.2, 0.5, 0.7, 1, 2, 3, 4, 5% or 
higher until a BIS™ value not less than 30 is reached or per Investigator’s 
discretion. The BIS™ value should be taken to at least 40, but not intentionally 
below 30.  
The equilibration time for each targeted plateau will be approximately 12 
minutes. The BIS™ value, MOAA/S score and Picture Recall test will be assessed 
when the patient is awake and prior to the induction of any anesthetic and at 
each ETSEVO concentrations with the exception of the Picture Recall test, which 
will just be completed at the first three steps. TES will then be initiated once 
the subject reaches a MOAA/S = 0, BIS™ value < 40 at the highest concentration 
of anesthesia anticipated. The BIS™ value will be recorded at the immediate 
end of the assessment and approximately 2 minutes following the TES 
assessment.   
ETSEVO is decreased by the same steps until consciousness is regained. 
Sevoflurane with Fentanyl Group, approximately 2 minutes before starting 
sevoflurane, to attain an effect-site targeted concentration of fentanyl of 2 

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ng/mL, an initial IV bolus of fentanyl will be given followed by the start of an 
infusion. Approximately within 10 minutes, the infusion rate of fentanyl may be 
adjusted to maintain the effect-site concentration of fentanyl of 2 ng/ml.  
Sevoflurane will be administered via a tight-face mask in steps to achieve a loss 
of consciousness by increasing the end-tidal concentration of sevoflurane 
(ETSEVO). Targeted concentration for ETSEVO are 0.2, 0.5, 0.7, 1, 2, 3, 4, 5% or 
higher until a BIS™ value not less than 30 is reached or per Investigator’s 
discretion. The BIS™ value should be taken to at least 40, but not intentionally 
below 30.   
The equilibration time for each targeted plateau will be at least 12 minutes.  
The BIS™ value, MOAA/S score and Picture Recall test will be assessed when 
the patient is awake and prior to the induction of any anesthetic and at each 
ETSEVO concentrations with the exception of the Picture Recall test, which will 
just be completed at the first three steps. TES will then be initiated once the 
subject reaches a MOAA/S = 0, BIS™ value <40 at the highest concentration of 
anesthesia anticipated. The BIS™ value will be recorded at the time of subject’s 
response and approximately 2 minutes following the TES assessment.   ETSEVO is 
decreased by the same steps until consciousness is regained. 
The cardiac output will be monitored, and subjects could be discontinued per 
PIs discretion. The respiratory rate of 4 breaths/minute or less will be 
considered evidence of fentanyl-induced respiratory depression, and fentanyl 
will be discontinued.  
Desflurane Group, Due to desflurane being a volatile agent and not well 
tolerated as an induction agent, an initial intravenous IV bolus of 1% propofol 
provided at 2mg/kg, with supplemental boluses given at the investigator’s 
discretion, in order to achieve LMA insertion. Propofol will be administered 0-
15 minutes prior to desflurane. Desflurane will then be administered via a tight-
face mask or LMA at the targeted end-tidal concentration of desflurane (ETDES) 
of 2, 5, 7, 8, 9, 10 %, or higher until a BIS™ value not less than 30 is reached or 
per Investigator’s discretion. The BIS™ value should be taken to at least 40, not 
intentionally below 30.   
The equilibration time for each targeted plateau will be approximately 12 
minutes. The BIS™ value and MOAA/S score will be assessed when the patient 
is awake and at the different ETDES concentrations. TES will then be initiated 
once the subject reaches a MOAA/S = 0, BIS™ value < 40 at the highest 
concentration of anesthesia anticipated. The BIS™ value will be recorded at the 
immediate end of the assessment and approximately 2 minutes following the 
TES assessment.   
The BIS™ value will be correlated with desflurane ETDES concentration. LMA 
should be removed at the highest level of sedation while maintaining subject’s 

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safety in order to allow for a gradual emergence from anesthesia. ETDES is 
decreased by the same steps until consciousness is regained. 
Isoflurane Group: Due to isoflurane being a volatile agent and not well 
tolerated as an induction agent, an initial IV bolus of 1% propofol provided at 
2mg/kg, with supplemental boluses given at the investigators discretion in 
order to achieve LMA insertion, will be administered 0-15 minutes prior to 
isoflurane.  Isoflurane will be administered via a tight-face mask or LMA in steps 
to achieve a loss of consciousness (MOAA/S of 0 or 1) by increasing the end-
tidal concentration of Isoflurane (ETISO). Targeted concentration for ETISO are 
0.2, 0.5, 0.7, 1, 1.5% or higher until a BIS™ value not less than 30 is reached or 
per Investigator’s discretion. The BIS™ value should not be taken to at least 40, 
not intentionally be taken below 30.  .  
The equilibration time for each targeted concentration will be approximately 12 
minutes to maintain a constant ETISO. The BIS™ value and MOAA/S score will be 
assessed when the patient is awake and at each ETISO concentrations. TES will 
then be initiated once the subject reaches a MOAA/S 0, BIS™ value < 40 at the 
highest concentration of anesthesia anticipated. The BIS™ value will be 
recorded at the immediate end of the assessment and approximately 2 minutes 
following the TES assessment. 
The BIS™ value will be correlated with the isoflurane ETISO concentration.  LMA 
should be removed at the highest level of sedation while maintaining subject’s 
safety in order to allow for a gradual emergence from anesthesia. ETISO is 
decreased by the same steps until consciousness is regained. 
The start time of any drug infusion, target effect-site concentrations, infusion 
rate, the start and end time of the assessment including BIS™ value prior to 
MOAA/S assessment, Picture Recall test and TES will be recorded in the 
electronic Case Report Forms (eCRFs). Any adjustments to the infusion rate and 
time of adjustment will be recorded, and any changes to subject management 
during the procedure will be noted on the eCRFs. 
Also, the device data (raw signals), including Heart Rate, Blood Pressure, 
Respiration Rate, EtCO2, SpO2, BIS™, TCI will be recorded in real-time during the 
procedure and files will be provided to Medtronic by the site. The instructions 
on the secure data transfer will be provided by Medtronic.  
Each subject will be contacted by phone within 48 hours after completion of 
the procedure to perform a safety assessment. 
Safety Assessments 
An anesthesiologist authorized to administer sedation drugs will be responsible 
for administering any procedural drugs for the sedation and monitoring of 
subject safety and physical state. All other personnel involved with the safety 
monitoring of subjects must be trained in and familiar with the management of 
recovery of sedated patients. The study site should have a setting that is fully 

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equipped for the monitoring and support of the respiratory and cardiovascular 
function. Subjects will be continuously monitored throughout the study. 
Subjects will be monitored for Adverse Events (AE) , Serious Adverse Events 
(SAE), and Device-Related Adverse Events from the BIS™ sensor application 
throughout the study and through the follow-up phone call. 
 Statistics 
Data will be analyzed by Medtronic or its designee. Any changes in statistical 
methods will be detailed in the Clinical Study Report.  
Standard demographic information and baseline characteristics will be 
summarized using descriptive statistics. For safety assessments, AEs will be 
summarized using frequency counts and percentages. Descriptive statistics will 
be provided by severity and relationship as needed.  
The primary effectiveness analysis will be based on all evaluable data collected 
from the left side of the brain to reflect the typical operation of the device from 
this study. The BIS™ index value collected from the right side of the brain will 
be used for research. 
All randomized subjects will be included in the analysis. For those subjects who 
do not complete a follow-up call, the analysis will include all data up to the last 
collected point or follow-up call. Subjects who completed the procedure phase 
will not be replaced. If the subject discontinues before randomization or during 
the procedure phase, she/he will be replaced. 
Any subject who responds to any verbal command with MOAA/S assessment 
score of 2, 3, 4, and 5 will be considered as responsive. Subjects with MOAA/S 
assessment scores of 0 and 1 will be considered unresponsive.  
The data will be analyzed for each regimen. The logistic model (simplified Emax 
model) will be used to analyze the relationship between the BIS™ index and loss 
of responsiveness through the probability of response curves. The values of 
BIS™, at which 50% (BIS50) and 95% (BIS95) of subjects are unresponsive, and 
their 95% confidence intervals will be derived. The systematic variance 
between groups will be evaluated. The Prediction Probability score (PK) for 
correctly predicting if the subject was responsive or unresponsive will be 
assessed.   
An interim review will be performed by MDT at the end of stage 1, when all (50 
subjects with 10 subjects per group) have completed the evaluation. Both the 
primary and secondary objectives will be evaluated during the interim review. 
One or more groups may be dropped upon interim results for safety concern 
(unacceptable safety events per clinical judgment).  
 
 
 

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4. Introduction  
1. 
 
2. 
 
3. 
 
4. 
 
4.1. 
Background  
4.1.2 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. General 
anesthesia is performed by medical professionals, generally anesthesiologists and nurse anesthetists, with 
extensive education and training in the physiology, pharmacology, techniques, and risks involved.  
 
Two critical components of general anesthesia are hypnosis and analgesia. Maintaining an adequate level 
of anesthesia depth is critical to the attenuation of these responses. The hypnotic component can be 
defined as the probability of tolerance to non-painful stimulus, e.g., name-calling, shaking, and shouting. 
The analgesic component may be considered as the probability of tolerance to a painful stimulus. 
Tolerance is the absence of a response, 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. Thus, it’s vital that the anesthesiologist 
know when a patient has reached a depth of anesthesia commensurate with an impending stimulus. 
Superficial or deep depth levels can be disastrous in both the short and long run when a patient expects 
a surgical procedure to be safe and painless, assured that throughout the procedure, they are asleep, 
without any perception or memory during that period. Intravenous anesthetics, including propofol, 
barbiturates, and benzodiazepines, produce a concentration-dependent reduction in wakefulness 
ultimately leading to complete loss of consciousness. The effective dose (ED50) of intravenous anesthetics 
for obtaining general anesthesia is calculated as the effect-site concentration at which 50 percent of 
patients will not respond upon noxious stimulation.  
 
This critical concentration aids in comparing the neurophysiologic effects of different drugs, both within 
and between different species. Inhalational anesthetics, including Isoflurane, Sevoflurane, and 
Desflurane, similarly have a designation for standardizing each agent’s concentration/effect relationship. 
The minimum alveolar concentration (MAC) is the concentration of volatile anesthetic that prevents 
movement in response to a standard skin incision in 50% of patients. Despite different mechanisms and 
sites of action, most anesthetic agents appear to cause unconsciousness by targeting, directly or indirectly, 
a posterior lateral corticothalamic complex centered around the inferior parietal lobe, and perhaps a 
medial cortical core of the brain.[3]  

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4.1.2 EEG Monitoring in Anesthesia 
Since 1939, anesthesiologists have known about changes in the electroencephalogram (EEG) that are 
produced by anesthetic agents.[4] 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 different 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. [5, 6] 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 prevent intraoperative awareness and help to ensure that an 
exact dose of anesthetic drugs is given. The lightness of anesthesia can result in the recall of events that 
happen in the operation 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 [7]. There is no objective scale that measures “too light” or “too 
deep” anesthesia. Bispectral Index (BIS) technology monitoring measures sedation depth based on 
changes in EEG signals and allows anesthesia providers to titrate general anesthesia to achieve the desired 
LOC on the brain [7, 8]. The BIS™ technology consists of a sensor placed on the patient’s forehead to 
measure the electrical signals from the cerebral cortex (the EEG), a digital signal converter to digitize the 
EEG, and derive the necessary processed EEG parameters, and a monitor to display the resultant BIS and 
EEG signal. BIS™ values quantify changes in the electrophysiologic state of the brain during anesthesia. 
BIS™ is a continuously processed EEG parameter that correlates to the patient’s level of hypnosis, where 
100 = awake and 0 = isoelectric 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. Overall, a BIS™ value below 60 is associated with a low probability of response 
to commands.[5, 9] Figure 1 reflects a general association between clinical state and BIS™ values. Ranges 
are based on results from a multi-center study [8] 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 

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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 
4.1.2 Clinical Summary  
The BIS™ system has been on the market for approximately 25 years, and there is a large amount of clinical 
data available to assess the performance and safety of the device. Table 1 summarizes overall clinical 
experience regarding the performance and safety of the BIS™ system in the published clinical literature 
carried out from May 2013 to September 2018. The safety clinical literature reviews accounted for 7,627 
patients and performance data for 43,247 patients. The patient populations included in these studies 
varied between infants, pediatrics, adults, obese adults, and the elderly.  
 
Table 1: Clinical Data from Literature 
Performance Data 
Safety Data 
Number of Publications 
Number of Patients 
Number of Publications 
Number of Patients 
32 publications addressing 
performance [10-41] 
43,247 
11 publications with safety 
data [11, 14, 20, 26, 27, 29, 
35-37, 42, 43] 
7,627 
 
The clinical literature review did not identify any new risks/side effects or safety concerns for the target 
device and its intended indications. The data form published clinical studies included in safety assessment, 
Table 1, did not reveal any new complications directly related to the use of the devices. 
 
4.2. 
Purpose 

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To investigate the relationship between BIS™ and inhaled anesthetics across a wide range of anesthetic 
concentration and hypnotic states, and to provide evidence to support BIS™ performance in use with 
sevoflurane, isoflurane and desflurane in combination with opioids. 
5. Objectives  
5. 
 
5.1. 
Objectives 
Primary Objective(s)  
To determine BIS50 (BIS™ value at which 50% of patients will be unresponsive at a given drug 
concentration)  
Secondary Objective(s)  
To determine BIS95 (BIS™ value at which 95% of patients will be unresponsive at a given drug 
concentration)  
To determine Prediction Probability (PK) for correctly predicting if the subject was responsive or 
unresponsive.  
6. Study Design  
This is a prospective, randomized study to collect data to evaluate the relationship between BIS™ and 
inhaled anesthetics without and with opioids. Five groups of anesthetic regimens will be studied as follow:  
1. Sevoflurane alone  
2. Sevoflurane with Remifentanil  
3. Sevoflurane with Fentanyl  
4. Desflurane alone  
5. Isoflurane alone 
Healthy Volunteers Subjects will be randomized to an anesthetic group. The BIS™ bilateral sensor will be 
placed on the subject’s forehead to study the effects of these drugs on the brain. Each subject will be 
given a sequential dose range of the target drug to achieve targeted drug concentration. At each steady-
state step, and after at least 12 minutes to achieve equilibrium, the Modified Observer's Assessment of 
Alertness/Sedation (MOAA/S) scale will be used to perform sedation/loss of consciousness assessment, 
with the Picture Recall test being used in the sevoflurane, sevoflurane with remifentanil and sevoflurane 
with fentanyl regimens to assess the subject’s level of anesthesia awareness, and Tetanic Electrical 
Stimulation (TES) being used if the patient is unresponsive to tactile stimuli (e.g., MOAA/S = 0, BIS™ value 

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< 40 at the highest concentration of anesthesia anticipated). The loss of tactile response will be defined 
according to the MOAA/S score value < 2 (0-1) and the presence of verbal response at values >2 (2-5).  
A training group, comprising of the first 2 - 4 subjects at each site will be enrolled to train the site team 
on the technology and to determine the quality of data collection, as required, before randomization. 
Afterward, randomization will proceed based on the Sponsor’s assessment of data quality.  
 
Subjects will have the effect of noxious electrical stimulation on the sedation state assessed for each arm 
once they achieve an MOAA/S score = 0, BIS™ value <40 at the highest concentration of anesthesia 
anticipated. The baseline BIS™ value will be recorded, followed by the MOAA/S assessment. Once TES is 
initiation, stimulation will start at 20mA, 50 Hz delivered for 1-5 seconds. If the subject does not 
purposefully (i.e. attempting to push the stimulus away) respond, the stimulation will increase to 30mA, 
50Hz for 1-5 seconds, then 40mA, 50Hz for 1-5 seconds and finally to 50mA, 50Hz for 1-5 seconds. If there 
is still no purposeful response, the subject will be considered a non-purposeful responder (i.e. exhibiting 
a reflex withdrawal, facial grimace, or groan) and their response such as withdrawal of extremity, facial 
grimace or other will be recorded along with the BIS™ value prior to stimulation, at the time of each 
stimulation and approximately 2 minutes following each stimulation. If the subject does respond to any 
of the stimulations with a purposeful response, the TES will be ended, the response will be noted and the 
BIS™ value will be recorded at the time TES is ended and at approximately 2 minutes following the 
stimulation. LMA should be removed at this point, if allowed per Investigator’s assessment without risk 
to subject. Anesthesia will then be decreased in the same steps until subject is conscious.  An 
anesthesiologist authorized to administer sedation drugs will be responsible for administering any 
procedural drugs for the sedation and monitoring of subject safety and physical state. All other personnel 
involved with the safety monitoring of subjects must be trained in and familiar with the management and 
recovery of sedated patients. The study site should utilize a setting that is fully equipped for the 
monitoring and support of the subject’s respiratory and cardiovascular functions. Subjects will be 
continuously monitored throughout the study. 
 
A two-stage design is used in this study. For each regimen group, 10 subjects will be enrolled in stage 1, 
and 20 subjects will be enrolled in stage 2. With 5 regimens, there will be a maximum of 150 subjects. An 
interim review will take place at the end of stage 1 (50 subjects and 10 subjects per regimen). Both the 
primary and secondary objectives will be evaluated during the interim review, and a particular group(s)  
may be dropped upon interim results for safety concerns (unacceptable safety events per clinical 
judgment) (refer to Section 12.)  
 
6. 
 
6.1. 
Duration 
Study duration is expected to be up to approximately 9 months. The expected duration of each subject’s 
participation is approximately 6 hours for both enrollment and procedure. The Enrollment Visit should 

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take approximately 2 hours to complete, and the Study Visit will be approximately 4 hours per subject. 
Each subject will be contacted by phone within 48 hours of the study participation.  
    
6.2. 
Rationale 
This clinical study is designed to capture the performance of BIS™ with anesthetic agents across a wide 
range of anesthetic concentrations and hypnotic states. The study design is deemed appropriate in this 
setting and will provide more information to confirm the performance and safety of the BIS™ monitoring 
system.  
 
The anesthetic regimens are selected based on clinical relevance. Inhalational anesthetics (e.g., isoflurane, 
sevoflurane and desflurane) can be used for the induction and maintenance of general anesthesia. Often 
inhaled anesthetics are used alone or in combination with other central nervous system depressants such 
as intravenous sedatives (e.g., propofol) and opioids (e.g., remifentanil and fentanyl.) During anesthesia, 
isoflurane, sevoflurane and desflurane can be maintained at end-tidal concentrations of 0.5 – 8% and 2.5 
- 16%, respectively, in combination with opioids.  
 
Intravenous (IV) opioids (e.g., remifentanil and fentanyl) are commonly used to provide analgesia and 
supplement sedation during general anesthesia. Opioids are often used in conjunction with volatile 
anesthetic agents and are typically not used alone during induction and maintenance of general 
anesthesia. The titration of the opioid doses can be facilitated by target-controlled infusion (TCI) pumps 
with the benefit that the recovery time from anesthetic doses can be appropriate for the individual patient 
and procedure. The TCI pump contains a microprocessor programmed with pharmacokinetic and 
pharmacodynamic models for relevant drugs. The user selects the drug and model to be used by that TCI 
pump and inputs the patient characteristics such as body weight and age, and the target plasma or ‘brain’ 
(effect-site) concentration, with the pump determining the initial bolus and subsequent infusion rates. 
The commonly used adult model remifentanil is Minto. For remifentanil, the induction levels of 4 ng/ml 
are commonly used, but the levels generally vary between 2-8 ng/ml. [44] For this study, the selected 
target effect-site concentration of remifentanil is 4 ng/ml to account for subject safety. During surgery, 
the effect-site concentration of fentanyl can vary. The effect-site concentrations of fentanyl between 0.8 
and 1.4 ng/ml are associated with numerous complaints of postoperative pain, and concentrations 3.0 
ng/ml and higher are associated with respiratory and cardiac depression. The optimal fentanyl effect-site 
concentration appears to be near 2 ng/ml [45].   
 
A two-stage design will be implemented, given the benefits of patient protection and sample size savings 
for more details, refer to Section 13.  
 
The de-identified data collected in this study also may be used for future product development. 

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7. Product Description 
7. 
 
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 BISx4™ unit. The BISx4™ unit filters and digitizes the signal, analyzes it for the artifact, and processes 
it using digital signal processing techniques to derive processed EEG parameters like BIS™, and finally 
sends the processed data to the monitor for display. The purpose of processing the EEG waveform data 
are to extract characteristic features from the complex signal that the BIS™ algorithm can utilize to 
ultimately derive BIS™. 
 
Table 2: System product/component information for the United States 
Product Number  Component (Manufacturer) 
Investigational or Market-released 
185-0151 
BIS™ Complete Monitor (Medtronic) 
Market-released 
185-1014-AMS 
BIS™ BISx4 (Medtronic) 
Market-released 
186-0107 
BIS™ Patient Interface Cable (Medtronic) 
Market-released 
N/A 
BIS™ Sensor (Medtronic) 
Market-released 
N/A 
BIS™ Detachable Power Cord (Medtronic) 
Market-released 
 
7.2. 
Manufacturer 
BIS™ Complete Monitoring System by (15 Hampshire St, Mansfield MA) Medtronic Inc.  
 
7.3. 
Packaging 
The Sponsor is responsible for the packaging and labeling of the devices for shipment to the study site. 
Research conducted for this study will utilize FDA-cleared (through the 510(k) regulatory process) devices. 
FDA-cleared devices are being used within the FDA-cleared indications for use and did not require special 
labeling.  
 
All equipment associated with the clinical study will be identified with visible markings stating, “For clinical 
trial use only.” Labeling of devices will be provided in accordance with local language requirements. 
 
7.4. 
Intended Population 

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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 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 Alfentanil, Desflurane,  
Fentanyl, Isoflurane, Midazolam, Nitrous Oxide, Propofol, Remifentanil, Sevoflurane and its usage with 
these anesthetic agents 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. 
 
Currently under investigation in this study is the validation of the BIS™ index as an aid in monitoring the 
effects of desflurane, isoflurane, propofol and sevoflurane with balanced anesthetic techniques for adult 
patients.  
7.5. 
Equipment 
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 then 
numerically displayed for the clinician’s use. The BIS Complete Monitoring System consists of the following 
components (Figure 2): 
• 
BIS™ Complete Monitor 
• 
BISx4™ (BISx4™ will be used in this study) 
• 
Patient Interface Cable (PIC)  
• 
BIS™ Sensor 
• 
Detachable Power Cord 

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Figure 2: The BIS™ Complete Monitoring System. 1 - Monitor Interface Cable; 2 - BIS™ Monitor; 3- BIS™ bilateral sensor will 
be used; 4- Patient Interface Cable (PIC); 5- BISx4™ (LoC 4 Channel) 
BISx4™ 
The BISx4™ 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 BISx4™ is 
shown in Figure 3. Its long flexible Monitor Interface Cable connects to the front of the monitor. The 
Patient Interface Cable (PIC) connects the BIS™ sensor to the BISx4™. The attachment clip on the BISx4™ 
is used to secure it in a convenient location near the patient's head. The BISx4™ Module is a variant of the 
BISx™ Module, and it processes up to four channels of EEG data. In this study, BISx4™ Module will be used 
with Bilateral Sensor. 
 
Figure 3: BISx4 - 1- Monitor Interface Cable connects to Monitor; 2- Patient Interface Cable connects to BIS sensor; 3- BISx4™ 
(BIS LoC 4 Channel)  
Patient Interface Cable 
Covidien BIS™ Sensor Patient Interface Cable (PIC) connects the BISx4™ to the BIS™ Sensor, refer to Figure 
3. 
 

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BIS™ Bilateral Sensor  
The sensor is the single-use component of the BIS™ Monitoring System and should be replaced after each 
use. BIS™ Bilateral Sensors are designed with a 6 electrode pre-gelled EEG electrode array that is applied 
directly to the patient’s forehead to transmit EEG signals to the BISx4™ Module. When the System is 
connected to a BISx4™ module and a BIS™ Bilateral Sensor, the monitor displays four channels of EEG. 
 
 
 
Figure 4: BIS™ Bilateral Sensor 
 
Other Equipment  
Additional equipment such as FDA-cleared Pulse Oximeter (SpO2 sensors and N600x monitors or other), 
capnography devices and a STIMPOD™ NMS450X nerve stimulator and TOF monitor may be provided by 
the sponsor to the study site. 
Site’s Equipment/Supplies  
Sevoflurane, isoflurane, desflurane, propofol, phenylephrine, ondansetron or other antiemetic / anti-
nausea medication, lidocaine, remifentanil, and fentanyl will be provided by the site. The remifentanil and 
fentanyl will be administered using the Total Intravenous Anesthesia (TIVA) method via the target-
controlled infusion (TCI) computer-controlled program, e.g., TIVA Trainer, or another computer-
controlled program. Other monitors will be used per site’s guidance or practice.  
 
7.6. 
Product Use 
A member of the Medtronic team will set up the BIS™ system at each participating research site or will 
guide the site in set up remotely in order to ensure all equipment is fully functional. Specific instructions 
for the Site Investigator and staff on system set up, 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 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 Principal Investigator at each participating site to ensure any staff performing 
tasks related to the clinical trial (e.g., Study Coordinators, Study Nurses, Sub-Investigators, etc.) have been 
appropriately trained, their training documented and included on the Delegation of Authority Log. 
 
7.8. 
Product Receipt and Tracking 
The investigator or designee will maintain records of devices/products provided by Medtronic free of 
charge delivery to the study site, e.g., device shipping forms. The following records will be maintained at 
a minimum for product delivery, receipt, and tracking at the site: dates, quantities received, lot/serial 
numbers, and expiration dates, as applicable.  
 
7.9. 
Product Storage 
Devices/products 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 outlined in this 
Clinical Investigation Plan. In addition, all information for the use, storage, and handling of the 
device/product as indicated in the Instructions for Use (IFU) and User Manual must be taken into account. 
Product Return 
Any devices provided by Medtronic free of charge, and all monitors and accessories should be returned 
to Medtronic and maintain documentation of return. Non-functioning investigational devices must be 
returned to Medtronic as soon as possible for investigation. Instructions for returning the device will be 
provided. 
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 Log in the Investigator Site File. On this log, the receipt, use, return, and disposal dates of 
the investigational devices/products and subject identification shall be documented. At the end of the 
clinical study, the principal investigator must sign and date the original Product Accountability Log.  

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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 investigators must be trained in the 
handling of 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 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:  
• 
Institutional Review Board (IRB) approval (and voting list, as required by local law) of the 
current version of the Clinical Investigational Plan (CIP) and Informed Consent Form (ICF)  
• 
Regulatory Authority (RA) approval or notification (as required per local law)  
• 
Fully executed Clinical Trial Agreement (CTA)  
• 
Financial disclosure  
• 
Curriculum Vitae (CV) of investigators and key members of the investigation study site team  

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• 
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 
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 under the supervision of a study investigator, but no data entry, shall be 
performed by Medtronic personnel or their representatives at study sites 
• 
Monitoring and auditing activities  
9. Selection of Subjects 
8. 
 
9. 
 
9.1. 
Study Population 
Up to 150 healthy, non-smoking (or has refrained from smoking for 2 days) volunteers, ages 18 to 60 
years, will be selected for this study. In each group, subjects will be distributed across genders as equally 
as practical. 
 
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 in order 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 they are determined to meet all eligibility criteria. Study enrollment is accomplished 
by signing of the informed consent and successfully passing the study inclusion/exclusion criteria and 
health screening evaluation. Subjects who sign informed consent, but are not enrolled, are considered 
screen failures. 
 
9.3. 
Inclusion Criteria 

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1) Healthy (ASA physical status 1), male or female subjects between the ages of 18 to 60 years; 
2) Completion of a health screening for a medical history by a licensed physician, nurse practitioner 
or physician assistant;  
3) Vital signs must be within the following ranges to be included: Vital signs measured sitting after 3 
minutes rest; heart rate: 45-90 bpm; systolic blood pressure: 110-140; diastolic blood pressure: 
50-90. Out-of-range vital signs may be repeated once. [Pre-dose vital signs will be assessed by the 
Principal Investigator or designee (e.g., a medically qualified sub-investigator) before study drug 
administration. The Principal Investigator or designee will verify the eligibility of each subject with 
out-of-range vital signs and document approval before dosing]. 
 
9.4. 
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 
[self-reported];  
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) [self-reported and assessment by PI or delegate]; 
3) Known cardiovascular disease (e.g., hypertension, coronary artery disease, prior acute myocardial 
infarction, any valvular and/or myocardial disease involving a decrease in ejection fraction, 
arrhythmias, which are either symptomatic or require continuous medication/ pacemaker/ 
automatic internal cardioverter defibrillator), current implanted pacemaker or automatic internal 
cardioverter defibrillator [self-reported and assessment by PI or delegate]; 
4) Has a clinically significant abnormal finding on medical history, physical examination, clinical 
laboratory tests, or ECG at the screening [self-reported and assessment by PI or delegate]; 
5) Use of psychoactive medication within the past 60 days (e.g., benzodiazepines, antiepileptic 
drugs, Parkinson’s medication, anti-depressant drugs, opioids) [self-reported and assessment by 
PI or delegate]; 
6) Subjects with known gastric diseases [self-reported and assessment by PI or delegate]; 
7) Has a positive urine cotinine test or urine drug screen or oral ethanol test [POC testing]; 
8) Known history of allergic or adverse response to drugs to be administered [self-reported];  
9) Known history of complications relating to previous general anesthesia or conscious sedation 
[self-reported and assessment by PI or delegate]; 
10) Known history of malignant hyperthermia [self-reported and assessment by PI or delegate]; 
11) Has a room air saturation less than 95% by pulse oximetry [measurement by PI or delegate]; 
12) Has a clinically significant abnormal pulmonary function test via spirometry [assessment by PI or 
delegate]; 

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13) Pregnant or lactating women [assessed by urine test and self-reported]; 
14) Subjects with tattooed skin specific to the sensor placement areas (forehead, fingers, chest) [self-
reported and assessment by PI or delegate]; 
15) The subject must not take any prescription medication, except female hormonal contraceptives 
or hormone replacement therapy, from 14 days before the dosing until the end-of-study visit 
without evaluation and approval by the Investigator. Subjects who participated in a previous 
clinical trial who received a required FDA approved concomitant medication, for example, 
naltrexone, but were not randomized may be considered for participation in this study if they 
meet the washout requirement [assessment by PI or delegate]. 
10.  Study Procedures  
10. 
 
10.1. 
Schedule of Events 
The Schedule of Events, Table 3, summarizes the intervals and data collection procedures.  
Table 3: Schedule of Events 
Study Tasks 
Pre-Screening 
Phone Visit 
Enrollment 
Visit 1 
Execution 
Visit 2 
Follow- up 
Phone Visit 
Pre-Procedure 
Randomization 
Procedure 
Eligibility Assessments 
Online or phone call pre-
screening 
x 
 
 
 
 
 
Informed Consent 1 
 
x 
 
 
 
 
Demographics  
 
x 
 
 
 
 
Medical History  
 
x 
 
 
 
 
Physical Exam  
 
x 
 
 
 
 
Pulmonary function test 
 
x 
 
 
 
 
Single 12-lead ECG 
 
x 
 
 
 
 
Urine sample for the 
presence of cotinine 
 
x 
x 
 
 
 
Urine pregnancy test 
(Female) 
 
x 
x 
 
 
 
Complete blood count 
 
x 
 
 
 
 
Inclusion/exclusion 
assessment 
 
x 
x 
 
 
 
Vital signs 
 
x 
x 
 
 
 
Concomitant Medication 
 
x 
x 
 
 
 
Urine drug screen and 
alcohol breathalyzer 
 
 
x 
 
 
 
Randomization to 
regimen group 
 
 
 
x 
 
 
Safety Monitoring  
 
 
 
 
x 
 
Sensors application 
 
 
 
 
x 
 
Patient monitoring 
including raw data 
collection 
 
 
 
 
x 
 

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Procedure with drug 
administration  
 
 
 
 
x 
 
BIS™, Picture Recall Test4, 
MOAA/S, TES assessments  
 
 
 
 
x 
 
Safety Assessments and Compensation 
Adverse Event 
Assessment 2 
 
x 
x 
 
x 
x 
Device Deficiency 3 
 
 
 
 
x 
 
Participant stipend  
 
 
x 
 
x 
 
 
1. Written informed consent must be obtained prior to any study-specific evaluations; for more 
details, refer to Section 10.3 
2. All Adverse Events, regardless of relatedness or outcome, will be collected and reported from the 
time of BIS™ sensor application through 48 hours following procedure; for more details, refer to 
Section 12 
3. Device Deficiency will be collected and reported; for more details, refer to Section 12. 
4. Picture Recall Assessment will only be performed in the sevoflurane, sevoflurane with 
remifentanil, and sevoflurane with fentanyl groups. 
 
10.2. 
Subject Pre-Screening/Screening 
Patients will be pre-screened for potential enrollment in the clinical study based on prior medical history 
and records. 
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. 
 
10.3. 
Subject Consent 
At the enrollment visit, subjects will be approached to obtain written informed consent prior to any data 
collection. Once the signed and dated Informed Consent Form (ICF) is collected, the screening of the 
subject will follow. The purpose of the study and the benefits and risks of the procedures will be explained 
to the subject, and the consent process must be documented. Subjects who agree to study participation 
must sign the Institutional Review Board (IRB) approved ICF. Consent to participate in this study must be 
given in writing. Subjects that are unable to give consent will not be included in the study. A sample copy 
of the ICF will be maintained under separate cover. 
 
The Investigator or authorized designee must obtain written informed consent before any clinical study 
related activity takes place. Prior to entry into the study, the IRB and Medtronic-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 each subject.  
The Investigator or authorized designee will fully inform the subject of all aspects of the clinical study that 
are relevant to the subject’s decision to participate in the clinical study (e.g., purpose and duration of the 

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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 subjects. The subject 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. All questions about the clinical study 
should be answered to the satisfaction of the subject. In the case that a subject is unable to read, an 
impartial witness must also be present and sign the informed consent to confirm that the research has 
been clearly explained and all of the subject’s questions have been answered.  
 
Neither the Investigator nor the investigation site staff shall coerce or unduly influence a subject 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. When the subject decides to participate in the clinical study, the 
HIPAA Form (if applicable) and the ICF must be personally signed and dated by the subject.  
 
After the subject has signed and dated the ICF, the Investigator must provide the subject with a copy.  
 
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 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. 
 
10.4. 
Enrollment - Visit 1 
After successful completion of the pre-screening, qualified subjects will be invited to attend Visit 1 to 
complete the ICF. The Investigator or designee will inform the prospective subjects on the study 
procedures and explain the consenting process. Once ICF is signed, the following will be performed during 
the screening: 
• 
Demographics (race, ethnicity, sex, height, weight, skin tone, calculated body mass index 
(BMI)) will be recorded on the eCRFs; 
• 
Medical History will be evaluated and documented to evaluate for prior or existing medical 
conditions and/or procedures that would exclude subjects from participation in the study; 
• 
Physical examination including an evaluation of general appearance, cardiovascular, 
respiratory musculoskeletal system, skin, neurologic function, and head, eyes, ears, nose and 
throat; 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 1 will be enrolled; 

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• 
Concomitant Medications, including the history of prescription and over the counter 
medication, will be carefully noted and recorded. Medication name, indication for use, dose, 
frequency, route of administration start/stop date will be recorded on the eCRFs; 
• 
Vital signs - Heart Rate, Systolic, and Diastolic Blood Pressures, Respiratory Rate and Oxygen 
Saturation (SpO2) will be evaluated;   
• 
Single 12-lead ECG;   
• 
Complete blood count (CBC); 
• 
Urinary pregnancy test; 
• 
A urine sample will be tested for the presence of cotinine (nicotine metabolite) to exclude 
smokers; 
• 
Subjects able to bear children will have to attest to birth control methods; 
• 
Adverse event review will be completed to assess events at baseline, and that occur after 
enrollment.   
The Enrollment results and informed consent will stay valid for 60 days.  
 
10.5. 
Execution – Visit 2 
Pre-Procedure  
• 
On the study day, subjects will arrive at the clinical research unit with appropriate fluid and solid 
intake as directed by study staff. The subject will be instructed not to consume beverages and 
foods containing alcohol, grapefruit, or caffeine/xanthine from 48 hours before dosing until the 
end-of-study visit. All volunteers will fast for at least 6 hours before the start of the drug 
administration. The per dosing instructions will be provided to the subject.  
• 
Any significant change in health status since Visit 1 will be recorded. 
• 
Concomitant Medication and adverse events will be checked. 
• 
All subjects will have urine drug screen and alcohol breathalyzer (Oral Ethanol) tests done.  
• 
Subjects of child-bearing potential will also have a urine pregnancy test done. 
• 
Review Inclusion and Exclusion Criteria re-checked based on additional information. 
• 
Enrollment Pass is based upon successful inclusion /exclusion criteria during Visits 1 and 2 with 
investigator sign-off. 
Randomization  
At Visit 2, all subjects who satisfy all the entry criteria will be equally randomized to each group of 
anesthetics regimens, stratifying by site. Randomization schedules will be created by an independent 
statistician, and randomization assignments will be automatically populated on the Randomization e-CRF. 
Once subjects are assigned to a study group, they are considered randomized.  All randomized subjects 
should be encouraged to comply with the study procedures until the end of the study.   

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Procedure  
Safety Monitoring 
For the subject’s safety, an anesthesiologist authorized to administer sedation drugs will be responsible 
for administering any procedural drugs for the sedation and monitoring of subject safety and physical 
state. All other personnel involved with the safety monitoring of subjects must be trained in and familiar 
with the management of recovery of sedated patients. The study site should utilize a setting that is fully 
equipped for the monitoring and support of the subject’s respiratory and cardiovascular function. Subjects 
will be continuously monitored throughout the study. 
All subjects will be monitored during procedure using an electrocardiogram (ECG), Pulse Oximeter for 
SpO2, and capnography (or another system) for Respiration Rate and EtCO2. A clinician will be monitoring 
respiratory and cardiac functions to determine if interventions are needed to maintain an adequate 
airway. The respiration support will be provided to ensure an unobstructed airway, adequate oxygenation 
(SpO2 >92%), and CO2 homeostasis throughout the study. As needed for airway support, the 
anesthesiologist may gently lift chin or jaw thrust (with or without manually assisted breathing), insertion 
of an airway device (oropharyngeal airway or laryngeal mask airway) and/or intermittent positive pressure 
ventilation (IPPV). Mask or nasal cannula will be used for supplemental O2 delivery.  
 
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 (PI).  
 Regimen Set-Up  
The opioids (remifentanil or fentanyl) will be administered via the target-controlled infusion (TCI) pump 
using either the preprogrammed pump protocols or computer-controlled program, e.g., TIVA Trainer, or 
another computer-controlled program, to ensure that the targeted effect-site concentration of a drug is 
reached and maintained at each drug concentration plateau. 1% propofol and remifentanil or fentanyl 
diluted to a single concentration of 50 µg/ml will be used in this study. The infusion rate between 0 and 
1200 ml/hr will be used to achieve a targeted concentration of remifentanil and fentanyl. For 
remifentanil, Minto [1, 46] PK/PD model will be used. The kinetic model for fentanyl will not be weight-
adjusted [2]. Phenylephrine may be provided at a concentration of 100 mcg/mL and lidocaine can be 
administered per Investigator discretion as a bolus over 3-5 seconds at a maximum concentration of 
100mg. Antiemetic / anti-nausea medication (i.e. Ondansetron) may be used prophylactically on all 
subjects at the investigator’s discretion.  
 
Inhalation anesthetic drugs will be administered via a tight-fitting face mask or a laryngeal mask (LMA). 
Subjects will be connected to a circular breathing system of an anesthesia machine. After the subject loses 
responsiveness, a laryngeal mask airway (LMA) may be inserted as needed to facilitate airway control at 

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deeper levels of anesthesia. Inhalation agents will be administered with O2 to maintain saturation of 
greater than 90%. 
Sensor Application 
The BIS™ sensor will be applied per its IFU. Subjects will have an intravenous catheter inserted for fluid 
and drug administration.  The TES sensor will be applied per its IFU. A stimulation of 2-5mA, 5 Hz for 1-5 
seconds or per IFU will be provided to ensure proper application 
 
The subject will rest for at least 12 minutes before starting any regimen. 
 
MOAA/S, Picture Recall Test and Tetanic Electrical Stimulation (TES) 
 
At each steady-state step and after equilibration, the MOAA/S assessment will be administered by an 
anesthesiologist. The same anesthesiologist, trained and delegated to perform the MOAA/S assessment 
on the Delegation of Tasks Log must perform all MOAA/S assessments for a specific subject, refer to 
Appendix A. The maximum number of delegated Anesthesiologists per site to perform the MOAA/S 
assessment is two in order to ensure consistency across physicians. 
 
Subjects in the sevoflurane, sevoflurane with remifentanil and sevoflurane with fentanyl regimens will 
then be assessed using a Picture Recall test consisting of showing each subject a standard set of 10 pictures 
form the OASIS image set at each steady state and after equilibrium. The first set of control pictures will 
be shown prior to the administration of any anesthetics and following the initial MOAA/S assessment. The 
second set of control pictures will be shown at the second steady-state step following the MOAA/S 
assessment and the third set of control pictures will be shown at the third steady-state step following the 
MOAA/S assessment. If the subject is still awake at the fourth step, they will be shown a fourth set of 
control pictures following the MOAA/S assessment.  At each step, the subject will be asked to confirm 
that they can see the pictures and if they are unable to open their eyes, the pictures will be shown and it 
will be noted that the pictures were not seen. Once the subject is deemed ready for discharge, they will 
be shown the 30-40 control pictures from the procedure in addition to 30 distractor pictures. It will be 
noted which pictures the subject was able to identify and whether they were control or distractor pictures. 
 
Each site will be provided with 7 standardized sets of pictures. Three (3) to 4 control sets will be shown 
during the procedure and 3 will serve as distractors. These control and distractor sets of pictures should 
be switched for every other subject. 
 
Subjects will receive noxious electrical stimulation using Tetanic Electrical Stimulation (TES) once they 
achieve a MOAA/S score = 0, BIS™ value < 40 at the highest concentration of anesthesia anticipated and 
have concluded the Picture Recall Test. The BIS™ value will be recorded, followed by the MOAA/S 

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assessment. Then, TES will be initiated following the Instructions for Use (IFU) for the XAVANT STIMPOD™ 
NMS 410/450X device.  TES will then be initiated once the subject reaches a MOAA/S 0, BIS™ value <40 at 
the highest concentration of anesthesia anticipated., Stimulation will start at 20mA, 50 Hz delivered for 
1-5 seconds. If the subject does not purposefully (i.e. attempting to push the stimulus away) respond, the 
stimulation will increase to 30mA, 50Hz for 1-5 seconds, then 40mA, 50Hz for 1-5 seconds and finally to 
50mA, 50Hz for 1-5 seconds. If there is still no purposeful response, the subject will be considered a non-
purposeful responder (i.e. exhibiting a reflex withdrawal, facial grimace, or groan) and their response such 
as withdrawal of extremity, facial grimace or other will be recorded along with the BIS™ value prior to 
stimulation, at the end of all assessments and approximately 2 minutes following all assessments. If the 
subject does respond to any of the stimulations with a purposeful response, the TES will be ended, the 
response will be noted and the BIS™ value will be recorded at the time TES is ended at approximately 2 
minutes following the stimulation. Anesthesia will then be decreased in the same steps until subject is 
conscious.   
Sevoflurane Group 
After approximately 2 minutes of baseline measurement, sevoflurane will be administered in steps to 
achieve a loss of consciousness via a tight-face mask by increasing the end-tidal concentration of 
Sevoflurane (ETSEVO). Targeted concentration for ETSEVO are 0.2, 0.5, 0.7, 1, 2, 3, 4, 5% or higher until a 
BIS™ value not less than 30 is reached or per Investigator’s discretion. The BIS™ value should  
be taken to at least 40, but not intentionally below 30.. The equilibration time for each targeted 
concentration will be approximately 12 minutes to maintain a constant ETSEVO.  
The BIS™ value, MOAA/S score and picture recall test will be assessed when the patient is awake and 
prior to the induction of anesthetic and at the different ETSEVO concentrations. TES will then be initiated 
once the subject reaches a MOAA/S =0 and the BIS™ value <40 at the highest concentration of 
anesthesia anticipated. The BIS™ value will be recorded at the time of subject’s response and 
approximately 2 minutes following the TES assessment.    
ETSEVO is decreased by the same steps until consciousness is regained.  
Sevoflurane with Remifentanil Group 
Approximately 2 minutes prior to starting sevoflurane, to attain an effect-site targeted concentration of 
remifentanil of 4 ng/ml, an initial IV bolus of remifentanil will be given followed by the start of an 
infusion. Approximately within 7 minutes, the infusion rate of remifentanil may be adjusted to maintain 
the effect-site concentration of remifentanil of 4 ng/ml.  
Sevoflurane will be administered via a tight-face mask in steps to achieve a loss of consciousness by 
increasing the end-tidal concentration of sevoflurane (ETSEVO). Targeted concentration for ETSEVO are 0.2, 

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0.5, 0.7, 1, 2, 3, 4, 5% or higher until a BIS™ value not less than 30 is reached or per Investigator’s 
discretion. The BIS™ value should be taken to at least 40, not intentionally below 30.    
The equilibration time for each targeted plateau will be approximately 12 minutes. The BIS™ value, 
MOAA/S score and picture recall test will be assessed when the patient is awake and at the different 
ETSEVO concentrations. TES will then be initiated once the subject reaches a MOAA/S = 0 and the BIS™ 
value < 40 at the highest concentration of anesthesia anticipated. The BIS™ value will be recorded at the 
time of subject’s response and approximately 2 minutes following the TES assessment.  
ETSEVO is decreased by the same steps until consciousness is regained. 
The cardiac output will be monitored, and subjects could be discontinued per PIs discretion. The 
respiratory rate of 4 breaths/min or less will be considered evidence of remifentanil-induced respiratory 
depression, and remifentanil will be discontinued.  
Sevoflurane with Fentanyl Group 
Approximately 2 minutes prior to starting sevoflurane, to attain an effect-site targeted concentration of 
fentanyl of 2 ng/mL, an initial IV bolus of fentanyl will be given followed by the start of an infusion. 
Approximately within 10 minutes, the infusion rate of fentanyl may be adjusted to maintain the effect-
site concentration of fentanyl of 2 ng/ml.  
Sevoflurane will be administered via a tight-face mask in steps to achieve a loss of consciousness by 
increasing the end-tidal concentration of sevoflurane (ETSEVO). Targeted concentration for ETSEVO are 0.2, 
0.5, 0.7, 1, 2, 3, 4, 5% or higher until a BIS™ value not less than 30 is reached or per Investigator’s 
discretion. The BIS™ value should be taken to at least 40, but not intentionally below 30.   
The equilibration time for each targeted plateau will be at least 12 minutes.  
The BIS™ value, MOAA/S score and picture recall test will be assessed when the patient is awake and at 
the different ETSEVO concentrations. TES will then be initiated once the subject reaches a MOAA/S = 0 
and the BIS™ value < 40 at the highest concentration of anesthesia anticipated. The BIS™ value will be 
recorded at the time of subject’s response and approximately 2 minutes following the TES assessment.   
ETSEVO is decreased by the same steps until consciousness is regained. 
The cardiac output will be monitored, and subjects could be discontinued per PIs discretion. The 
respiratory rate of 4 breaths/minute or less will be considered evidence of fentanyl-induced respiratory 
depression, and fentanyl will be discontinued.  
Desflurane Group 
Due to desflurane being a volatile agent and not well tolerated as an induction agent, an initial IV bolus 
of 1% propofol provided at 2mg/kg, with supplemental boluses given at the investigators discretion in 

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order to achieve LMA insertion, will be administered 0-15 minutes prior to desflurane. Per Investigator’s 
discretion and allowed by subject safety, once correct LMA placement has been confirmed, there will be 
an equilibrium time of approximately 15-20 minutes to allow the effect site concentration of propofol to 
reach a level consistent with a pharmacodynamic effect of consciousness as measured by a  MOAA/S 
score of 2 or 3. Desflurane will then be administered via a tight-face mask at the targeted end-tidal 
concentration (ETDES) of 2, 5, 7, 8, 9, 10 %, or higher until a BIS™ value not less than 30 is reached or per 
Investigator’s discretion. The BIS™ value should not intentionally be taken below 30.  
The equilibration time for each targeted plateau will be approximately 12 minutes. The BIS™ value and 
MOAA/S score will be assessed when the patient is awake and at the different ETDES concentrations. TES 
will then be initiated once the subject reaches a MOAA/S = 0 and the BIS™ value < 40 at the highest 
concentration of anesthesia anticipated. The BIS™ value will be recorded at the time of subject’s 
response and approximately 2 minutes following the TES assessment.   
The BIS™ value will be correlated with desflurane ETDES concentration. LMA should be removed at the 
highest level of sedation while maintaining subject’s safety in order to allow for a gradual emergence 
from anesthesia. ETDES is decreased by the same steps until consciousness is regained. 
Isoflurane Group 
Due to isoflurane being a volatile agent and not well tolerated as an induction agent, an initial IV bolus 
of 1% propofol provided at 2mg/kg, with supplemental boluses given at the investigators discretion in 
order to achieve LMA insertion, will be administered 15-20 minutes prior to isoflurane. Per Investigator’s 
discretion and allowed by subject safety, once correct LMA placement has been confirmed, there will be 
an equilibrium time of approximately 15-20 minutes to allow the effect site concentration of propofol to 
reach a level consistent with a pharmacodynamic effect of consciousness as measured by a  MOAA/S 
score of 2 or 3. Isoflurane will be administered via a tight-face mask in steps to achieve a loss of 
consciousness (MOAA/S of 0,1) by increasing the end-tidal concentration of Isoflurane (ETISO). Targeted 
concentration for ETISO are 0.25, 0.5, 0.75, 1, 1.5% or higher until a BIS™ value not less than 30 is reached 
or per Investigator’s discretion. The BIS™ value should be taken to at least 40, but not intentionally 
below 30.    
The equilibration time for each targeted concentration will be approximately 12 minutes to maintain a 
constant ETISO. The BIS™ value and MOAA/S score will be assessed when the patient is awake and at the 
different ETISO concentrations. TES will then be initiated once the subject reaches a MOAA/S = 0 and the 
BIS™ value < 40 at the highest concentration of anesthesia anticipated. The BIS™ value will be recorded 
at the time of subject’s response and approximately 2 minutes following the TES assessment.   
The BIS™ value will be correlated with desflurane ETISO concentration. LMA should be removed at the 
highest level of sedation while maintaining subject’s safety in order to allow for a gradual emergence 
from anesthesia. ETISO is decreased by the same steps until consciousness is regained. 

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eCRF Data Collection 
The start time of any drug infusion, target effect-site concentrations, infusion rate, the start and end times 
of the assessments including BIS™ value prior to and after MOAA/S and TES assessments will be recorded 
in the electronic Case Report Forms (eCRFs). Any adjustments to the infusion rate and time of adjustment 
will be recorded, and any changes to subject management during the procedure will be noted on the 
eCRFs. 
Raw Device Data Collection 
The device data (raw signals), including Heart Rate, Blood Pressure, Respiration Rate, EtCO2, SpO2, BIS™, 
TCI if available, will be collected in real-time during the procedure. The BIS™ data will be recorded with a 
USB memory stick connected to the monitor. Periodically, the raw device data will be transferred directly 
to the Medtronic secure server for data quality review and analysis. The instructions on the secure data 
transfer will be provided by Medtronic.  
 
10.6. 
Follow-up  
Phone Call 
The site will attempt to contact each subject by phone within 48 hours after completion of the procedure 
to perform a safety assessment. At least three attempts, phone, email or text, should be made to contact 
the subject. Each attempt should be clearly documented in the source documents, and the response or 
lack thereof should be captured.  
 
The safety assessment will include asking the subject the following questions:  
• 
Have you had any medical problems since your discharge from the clinical research unit?  
• 
Have you taken any medications (either prescribed or self-medicated) since discharge from the 
clinical research unit?  
 
10.7. 
Assessment of Efficacy 
Refer to Section 14. 
 
10.8. 
Assessment of Safety 
For safety analyses, adverse events will be summarized using frequency counts and percentages, refer to 
Section 14. 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. For device-related events refer to 
Section 12 . Adverse events occurring from the time of BIS™ sensor application to 48 hours after the 
procedure will be recorded. For AEs and AE reporting requirements, refer to Section 12. 
 

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10.9. 
Recording Data 
The study will utilize the electronic Case Report Forms (eCRFs) in a database provided by the Sponsor. All 
eCRFs will be completed using the assigned subject identification number.    
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). 
 
10.10. 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; 
• 
Serious Adverse Event/Serious Adverse Device Effect/Unanticipated Adverse Device Effect 
/Unanticipated Serious Adverse Device Effect reporting (for reporting refer to Section 12). 
 
Deviations will be recorded at the site and reported to Medtronic on the eCRF. The deviation 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 

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• 
description of deviation 
• 
date of occurrence 
• 
reason for the deviation 
• 
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. 
 
10.11. Subject Exit, Withdrawal or Discontinuation  
There are many scenarios in which a subject may exit the study. The following terms are used for 
withdrawal and completion: 
• 
Screen Failure: Did not meet the study inclusion/exclusion criteria;  
• 
Study Withdrawal: Removal from the study after Enrollment by either subject, PI, or Sponsor, or 
technical problems;  
• 
Study Complete: Completion of all study related activity by the subject; 
• 
Lost to Follow up: Subjects lost to follow-up will be documented.  
The investigator should make every attempt to contact the subject to have the subject complete the 
follow-up phone call within 48 hours or to determine the occurrence/resolution of adverse events (if any) 
refer to Section 9.6. 
It is the subject’s 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. All subjects will be encouraged to remain in the study through the follow-up phone call.  

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If the subject discontinues participating in the study prior to 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. 
11. Risks and Benefits 
11. 
 
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.  
  
11.2. 
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:  
• 
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.  
 
Some Sensor Warnings and Cautions are listed below, for more information on warnings and cautions, 
refer to Sensor IFU. 
 
Warnings:  

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• 
To reduce the hazard of burns during use of brain-stimulating devices (e.g., transcranial electrical 
motor evoked potential), place stimulating electrodes as far as possible from the bis sensor and 
place sensor according to instructions. 
 
Cautions: 
• 
Patient position may increase the risk of skin irritation on the forehead. With patients in prone 
position, consider minimizing pressure on the sensor. 
• 
Do not use if sensor is dry. 
• 
To avoid dry out, do not open pack until ready for use.  
• 
Due to intimate skin contact, reuse may pose risk of infection.  
• 
If skin rash or other unusual symptoms develop, stop use and remove.  
• 
Limited to short-term use (maximum 24 hours).  
• 
Do not cut sensor, as this will result in improper operation.  
• 
Upon removal, slight redness of skin may occur and typically resolves within a short period of 
time. 
 
11.3. 
BIS™ Monitoring System Risks 
Monitoring System will be used per IFU. Some warnings are listed below, for more information on 
warnings and cautions refer to IFU. 
 
Warnings:  
• 
Explosion hazard: do not use the BIS™ complete system in a flammable atmosphere or where 
concentrations of flammable anesthetics may occur.  
• 
Monitor is not designed for use in MRI environment.  
• 
Use only the power cord supplied by the manufacturer. Never adapt the plug from the monitor 
to fit a non-standard outlet.  
• 
U.S.A. requirement: for proper grounding, the power receptacle must be a three-wire grounded 
outlet. A hospital grade outlet is required. Never adapt the three-prong plug from the monitor to 
fit a two-slot outlet. If the outlet has only two slots, make sure that it is replaced with a three-slot 
grounded outlet before attempting to operate the monitor.  
• 
If the integrity of the external protective earth ground is in doubt, the BIS™ complete system shall 
be operated from its internal battery power source only.  
• 
Be sure the monitor is mounted securely in place to avoid personal or patient injury.  
• 
The BIS™ complete monitor should not be used adjacent to or stacked with other equipment. If 
adjacent or stacked use is necessary, the BIS™ complete monitor should be observed to verify 
normal operation in the configuration in which it will be used.  
• 
When connecting external equipment (e.g., data capture computer), the system leakage current 
must be checked and must be less than the IEC 60601-1-1 limit.  
• 
Using accessories other than those specified may result in increased electromagnetic emissions 
or decreased electromagnetic immunity of the BIS™ complete monitoring System.  

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• 
The use of accessory equipment not complying with the equivalent safety requirements of this 
equipment may lead to a reduced level of safety of the resulting system. Consideration relating 
to the choice shall include: Use of the accessory in the patient vicinity. Evidence that the safety 
certification of the accessory has been performed in accordance to the appropriate IEC 60601-1 
and/or IEC 60601-1-1 harmonized national standard.  
• 
Due to elevated surface temperature, do not place the BISx™ unit in prolonged direct contact with 
patient’s skin, as it may cause discomfort.  
• 
The conductive parts of electrodes or sensor and connectors should not contact other conductive 
parts, including earth.  
• 
To reduce the hazard of burns during use of high-frequency surgical equipment, the sensor or 
electrodes should not be located between the surgical site and the electro-surgical unit return 
electrode.  
• 
To reduce the hazard of burns during use of brain-stimulating devices (e.g., transcranial electrical 
motor evoked potential), place stimulating electrodes as far as possible from the BIS™ sensor and 
make certain that sensor is placed according to package instructions. The sensor must not be 
located between defibrillator pads when a defibrillator is used on a patient connected to the BIS™ 
complete system.  
• 
To minimize the risk of patient strangulation, the patient interface cable (PIC) must be carefully 
placed and secured.  
• 
Shock Hazard: Do not attempt to disconnect the power cord with wet hands. Make certain that 
your hands are clean and dry before touching the power cord.  
• 
Universal precautions shall be observed to prevent contact with blood or other potentially 
infectious materials. Place contaminated materials in regulated waste container.  
• 
Do not mix disinfecting solutions (e.g., bleach and ammonia), as hazardous gases may result.  
• 
Electrical Shock Hazard: Do not remove monitor covers during operation or while power is 
connected to monitor.  
• 
Electrical Shock Hazard: The manufacturer's inspection of this apparatus verified that the ground 
leakage current and the patient safety current were less than the specified limits established by 
the applicable safety standards. As a matter of safe practice, the institution should conduct 
periodic tests to verify these currents.  
• 
Whenever an event such as spillage of blood or solutions occurs, re-test ground leakage current 
before further use.  
• 
Leakage current must be checked by a qualified biomedical engineering technician whenever 
instrument case is opened.  
• 
Power supply is internally fused. Replace power supply only with Covidien BIS™ Complete power 
supply.  
• 
Portable RF communications equipment (including peripherals such as antenna cables and 
external antennas) should be used no closer than 30 cm (12 inches) to any part of the BIS™ 
complete monitoring system, including cables specified by the manufacturer. Otherwise, 
degradation of the performance of this equipment could result.  
• 
Check Target Range alarm limits to ensure they are appropriate for the patient being monitored 
with each use. Ensure Target Range alarm limits do not exceed the standard thresholds set by the 
institution.  

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• 
Do not decrease the adjustable alarm volume below ambient sound levels. Decreasing the alarm 
volume below ambient levels may compromise patient safety.  
• 
Explosion hazard: do not use the BIS™ complete system in a flammable atmosphere or where 
concentrations of flammable anesthetics may occur.  
• 
Use only the power cord supplied by the manufacturer. Never adapt the plug from the monitor 
to fit a non-standard outlet.  
• 
If the integrity of the external protective earth ground is in doubt, the BIS™ complete monitor 
shall be operated from its internal battery power source only.  
• 
Due to elevated surface temperature, do not place BISx™ unit in prolonged direct contact with 
patient’s skin, as it may cause discomfort.  
• 
The conductive parts of electrodes or sensor and connectors should not contact other conductive 
parts, including earth.  
• 
To reduce the hazard of burns during use of high-frequency surgical equipment, the sensor or 
electrodes should not be located between the surgical site and the electro-surgical unit return 
electrode.  
• 
The sensor must not be located between defibrillator pads when a defibrillator is used on a 
patient connected to the BIS™ complete system.  
• 
Check Target Range alarm limits to ensure they are appropriate for the patient being monitored 
with each use. Ensure Target Range alarm limits do not exceed the standard thresholds set by the 
institution.  
• 
Universal precautions shall be observed to prevent contact with blood or other potentially 
infectious materials. Contaminated materials should be disposed of in accordance with national 
and local waste disposal legislation and requirements.  
• 
Do not mix disinfecting solutions (e.g., bleach and ammonia) as hazardous gases may result.  
• 
Leakage current must be checked by a qualified biomedical engineering technician whenever an 
instrument case is opened.  
• 
A power supply is internally fused. Replace power supply only with Covidien BIS™ complete power 
supply.  
• 
Electrical Shock Hazard: The manufacturer’s inspection of this apparatus verified that the ground 
leakage current and the patient safety current were less than the specified limits established by 
the applicable safety standards. As a matter of safe practice, the institution should conduct 
periodic tests to verify these currents. Whenever an event such as spillage of blood or solutions 
occurs, re-test before further use.  
• 
Using accessories other than those specified may result in increased electromagnetic emissions 
or decreased electromagnetic immunity of the BIS™ complete monitoring system.  
• 
The BIS™ complete system should not be used adjacent to or stacked with other equipment. If 
adjacent or stacked use is necessary, the BIS™ complete monitor should be observed to verify 
normal operation in the configuration in which it will be used.  
 
11.4. 
XAVANT STIMPOD™ Quantitative NMT Monitor 
STIMPOD™ Quantitative NMT monitor will be used per IFU. Some warnings are listed below, for more 
information on warnings and cautions refer to the IFU. 

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Warnings: 
• 
Use of cables or accessories other than those supplied with the STIMPOD may result in serious 
injury. 
• 
Maintenance on this device may only be performed by the manufacturer or persons explicitly 
authorized by the manufacturer. 
• 
Do not use the STIMPOD in close proximity to equipment that produces strong electromagnetic 
fields, such as high frequency surgical equipment. The cable leads could act as an antennae and 
dangerous currents could be induced as a result. 
• 
Do not apply the STIMPOD to patients with implanted electrical devices, such as cardiac 
pacemakers, without first consulting with an appropriate medical specialist. 
• 
The device should not be used adjacent to or stacked with other equipment and that if adjacent 
or stacked use is necessary, the device should be observed to verify normal operation in the 
configuration in which it will be used. 
• 
The patient should avoid contact with metallic objects that are grounded, produce an electrical 
conductive connection with other equipment and/or enable capacitive coupling. 
• 
The cables should be positioned in such a way that they do not contact either the patient or other 
cables. 
• 
Simultaneous connection of a patient to high frequency surgical ME equipment and the STIMPOD 
may result in burns and possible damage to the stimulator. 
• 
Operation in close proximity (e.g. 1m) to a shortwave or microwave therapy ME equipment may 
produce instability in the stimulator output. 
• 
Application of electrodes near the thorax may increase the risk of cardiac fibrillation. 
• 
No modification of the equipment is allowed. 
• 
Do not modify this equipment without authorization of the manufacturer. 
• 
If this equipment is modified, appropriate inspection and testing must be conducted to ensure 
continued safe use of the equipment. 
 
11.5. 
Nellcor™ Pulse Oximeter 
Nellcor™ Pulse Oximetry will be used per IFU. Some warnings are listed below, for more information on 
warnings and cautions refer to IFU. 
• 
Pulse and Tissue Oximetry Sensor placement involves positioning pulse and tissue oximetry 
sensors on the subject in the same manner that is used on hospitalized subjects. 
• 
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. 

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• 
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 minor. 
• 
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.  
 
11.6. 
General Anesthesia Risks 
There are some risks associated with general anesthetics, but the anesthetics under study are relatively 
safe when administered correctly. Although not all of these side effects may occur, if they do occur, they 
may need medical attention. 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, and 
difficulty passing urine. These may occur despite the best efforts to avoid them. For additional information 
related to potential medication, risks refer to Table 4.  
 
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. 
 
Table 4: Possible Side Effects using Medication 
Possible side effects of remifentanil but not limited to: 
 
• 
Blurred vision  
• 
Chest pain or discomfort  
• 
Confusion  
• 
Difficult or troubled breathing  
• 
Dizziness, faintness, or lightheadedness 
when getting up suddenly from a lying or 
sitting position  
Less common side effects of remifentanil but not limited to: 
 
• 
Bluish lips or skin  
• 
Chills  
• 
Decreased cardiac output  
• 
Fast, pounding, or heartbeat or pulse  
• 
Feeling of warmth  
• 
Fever  
• 
Headache  
• 
Nausea or vomiting  

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• 
Irregular, fast or slow, or shallow 
breathing  
• 
Lightheadedness, dizziness, or fainting  
• 
Muscle stiffness or tightness  
• 
Pale or blue lips, fingernails, or skin  
• 
Shortness of breath  
• 
Slow or irregular heartbeat  
• 
Sweating  
• 
Unusual tiredness or weakness 
• 
Itchiness 
 
 
• 
Nervousness  
• 
Not breathing  
• 
Pain after surgery  
• 
Pain in the shoulders, arms, jaw, or neck  
• 
Pounding in the ears  
• 
Problems with bleeding or clotting  
• 
Redness of the face, neck, arms, and 
occasionally, upper chest  
• 
Shivering  
• 
Allergic reactions 
 
Possible side effects of fentanyl but not limited to: 
• 
Black, tarry stools 
• 
Blurred vision 
• 
Chest pain 
• 
Confusion 
• 
Convulsions 
• 
Cough 
• 
Decreased urine 
• 
Difficult or labored breathing 
• 
Dizziness 
• 
Dry mouth 
• 
Fainting 
• 
Fever or chills 
• 
Increased thirst 
• 
Irregular heartbeat 
• 
Lightheadedness 
• 
Loss of appetite 
• 
Lower back or side pain 
• 
Mood changes 
• 
Headache 
• 
Muscle pain or cramps 
• 
Nausea or vomiting 
• 
Nervousness 
• 
Numbness or tingling in the hands, feet, or lips 
• 
Painful or difficult urination 
• 
Pale skin 
• 
Pounding in the ears 
• 
Rapid breathing 
• 
Sneezing 
• 
Sore throat 
• 
Sunken eyes 
• 
Swelling of the hands, ankles, feet, or lower legs 
• 
Tightness in the chest 
• 
Troubled breathing with exertion 
• 
Ulcers, sores, or white spots in the mouth 
Less common side effects of fentanyl but not limited to: 
• 
Abdominal or stomach pain 
• 
Change in walking and balance 
• 
Clumsiness or unsteadiness 
• 
Decreased awareness or responsiveness 
• 
Decreased frequency of urination 
• 
Headache 
• 
Muscle twitching or jerking 
• 
Pounding in the ears 
• 
Rhythmic movement of the muscles 
• 
Seeing, hearing, or feeling things that are not there 
• 
Seizures 
• 
Severe constipation 
• 
Severe sleepiness 
• 
Shakiness in the legs, arms, hands, or feet 
• 
Slow or fast heartbeat 
• 
Thinking abnormalities 
• 
Trembling or shaking of the hands or feet 
 

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• 
Unusual tiredness or weakness 
• 
Wrinkled skin 
Possible side effects of sevoflurane but not limited to: 
• 
cough 
• 
Dizziness 
• 
Drowsiness 
• 
Increased amount of saliva 
• 
Nausea /vomiting 
• 
Shivering 
• 
Laryngospasm  
• 
Airway obstruction  
• 
Breath holding  
• 
Apnea 
• 
Respiratory disorder 
• 
Headache 
• 
Hypotension 
• 
Hypertension  
• 
Agitation 
• 
Bradycardia 
• 
Hypotension  
• 
Bradycardia 
• 
Tachycardia  
• 
Malignant hyperthermia 
Less common side effects of sevoflurane but not limited to: 
• 
Dry mouth 
• 
Arrhythmia, 
ventricular 
extrasystoles, 
supraventricular extrasystoles, complete AV block, 
bigeminy, inverted T wave, atrial fibrillation, atrial 
arrhythmia, second degree AV block, S-T depressed, 
extrasystoles 
• 
Sputum increased, hypoxia, wheezing, 
bronchospasm, 
hyperventilation, 
pharyngitis, 
hiccup, 
hypoventilation, 
dyspnea, stridor, hypoxia, asthma 
• 
Pulmonary edema 
• 
Increases in LDH, alkaline phosphatase, 
hypophosphatemia, acidosis, hyperglycemia 
• 
Blood glucose abnormal 
• 
Urination impaired, urine abnormality, urinary 
retention, oliguria 
• 
Rash 
• 
Muscle twitching  
• 
Syncope, hypertonia, taste perversion 
• 
Seizures, dystonia 
• 
Asthenia, pain, fluorosis 
• 
Allergic reactions 
Possible side effects of desflurane but not limited to:   
• 
Bluish lips or skin 
• 
Body aches or pain 
• 
Congestion 
• 
Cough 
• 
Dryness or soreness of the throat 
• 
Fever 
• 
Hoarseness 
• 
Not breathing 
• 
Runny nose 
• 
Tender, swollen glands in the neck 
• 
Tightness in the chest 
• 
Trouble breathing 
• 
Trouble swallowing 
• 
Voice changes 
Less common side effects of desflurane but not limited to:  
• 
Blurred vision 
• 
Chest pain or discomfort 
• 
Dizziness 
• 
Fast, pounding, or irregular heartbeat or pulse 
• 
Headache 
• 
Lightheadedness, dizziness, or fainting 
• 
Nervousness 
• 
Pounding in the ears 
• 
Slow or irregular heartbeat 
• 
Unusual tiredness 
• 
Allergic reactions 
 
Possible side effects of isoflurane but not limited to:   
• 
Nausea 
• 
Vomiting 
• 
Shivering 
 
Less common side effects of isoflurane but not limited to:  
• 
Dose-dependent hypotension 
• 
Arrhythmias 
• 
Malignant hyperthermia 
• 
Elevations in white blood cells 
• 
Decrease in creatinine and increase BUN 

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• 
Ileus, severe 
• 
Hepatic dysfunction 
• 
Respiratory depression 
 
Possible side effects of propofol but not limited to 
• 
Hypotension 
• 
Apnea lasting 30-60 sec  
• 
Apnea lasting >60 sec 
• 
Movement  
• 
Injection site burning/stinging/pain  
• 
Respiratory acidosis during weaning  
• 
Hypertriglyceridemia  
• 
Hypertension 
• 
Rash  
• 
Pruritus  
• 
Arrhythmia  
• 
Bradycardia  
• 
Cardiac output decreased concurrent opioid use 
increases incidence) 
• 
Tachycardia  
Less common side effects of propofol but not limited to 
• 
Arterial hypotension 
• 
Anaphylaxis 
• 
Asystole 
• 
Bronchospasm 
• 
Cardiac arrest 
• 
Seizures 
• 
Opisthotic rxn 
• 
Pancreatitis 
• 
Pulmonary edema 
• 
Phlebitis 
• 
Thrombosis 
• 
Renal tubular toxicity 
• 
Allergic reactions 
Possible side effects of lidocaine but not limited to 
• 
Hypotension 
• 
Edema  
• 
Injection site burning/stinging/pain  
• 
Small purple or red spots on skin 
• 
Skin irritation 
• 
Constipation 
• 
Nausea 
• 
Vomiting  
• 
Confusion  
• 
Dizziness  
• 
Headache 
• 
Numbness and tingling 
• 
Drowsiness 
• 
Tremor 
• 
  
Less common side effects of lidocaine but not limited to 
• 
Cardiac Arrest 
• 
Abnormal Heartbeat 
• 
Methemoglobinemia 
• 
Seizures 
• 
Severe allergic reaction 
• 
Malignant hyperthermia 
Possible side effects of phenylepherine but not limited to 
• 
Blurred vision 
• 
Chest pain or discomfort 
• 
Difficult or labored breathing 
• 
Dizziness 
• 
Fainting 
• 
Fast, slow or irregular heartbeat 
• 
Headache 
• 
Nausea or vomiting 
• 
Nervousness 
• 
Pain in shoulders, arms, jaws or neck 
• 
Pounding in the ears 
Less common side effects of phenylepherine but not limited to 
• 
Feeling of fullness in the head 
• 
Pounding or rapid pulse 
• 
Tingling in the arms or legs 
• 
Vomiting  

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• 
Sweating 
• 
Tightness in the chest 
• 
Unusual tiredness  
Possible side effects of ondansetron but not limited to 
• 
headache 
• 
constipation 
• 
weakness 
• 
tiredness 
• 
chills 
• 
drowsiness 
Less common side effects of ondansetron but not limited to 
• 
blurred vision or vision loss 
• 
rash 
• 
hives 
• 
itching 
• 
swelling of the eyes, face, lips, tongue, throat, hands, 
feet, ankles, or lower legs 
• 
hoarseness 
• 
difficulty breathing or swallowing 
• 
chest pain 
• 
shortness of breath 
• 
dizziness, light-headedness, or fainting 
• 
fast, slow or irregular heartbeat 
• 
agitation 
• 
hallucinations (seeing things or hearing voices that do 
not exist) 
• 
fever 
• 
excessive sweating 
• 
confusion 
• 
nausea, vomiting, or diarrhea 
• 
loss of coordination 
• 
stiff or twitching muscles 
• 
seizures 
• 
coma (loss of consciousness) 
 
11.7. 
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. 
 
11.8. 
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 investigational device 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 investigational device 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;  
 
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 

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• 
The investigational device is not for a 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 investigational device does not otherwise present a potential for serious risk to the 
health, safety, or welfare of a subject.  
 
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.  
12. Adverse Events and Device Deficiencies 
 
12.1. 
Adverse Events 
AE definitions are provided in Table 5. AEs will be collected throughout the study from the BIS™ sensor 
application through 48 hours following procedure. A list of anticipated adverse events and risks that are 
expected in nature is included in Section 11.  
 
Adverse Event assessment for the purposes of this study will cease after the follow-up phone call within 
48 hours after the procedure. All AEs considered at least possibly related to the study will be followed 
until resolved, stabilized, and/or returned to baseline. 
Reporting of these events to Medtronic will occur on an AE Form. 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 6), initial reporting may be done by phone, fax, or on 
the CRF completing as much information as possible. The completed AE CRF must be submitted to 
Medtronic as soon as possible.   
 
Any medication/treatment associated with the treatment of an AE must be reported.  
Subject deaths are also required to be reported.  
 
12.2. 
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. 

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DD that did not lead to an AE but could have led to a SADE (i.e., if suitable action had not been taken, if 
intervention had not been made, or if the circumstances had been less fortunate) require immediate 
reporting (see Table 5). 
 
12.3. 
Processing Updates and Resolution 
For any changes in status of a previously reported adverse event or DD (i.e. change in actions taken, 
change in outcome, change in relatedness), information needs to be updated on, or added to the original 
AE or DD form. All AEs must be followed until the AE has been resolved, is unresolved with no further 
actions planned, the subject exits the study, or until study closure, whichever occurs first.  
In the event that a subject is exited from the  study prior to study completion, all efforts should be made 
to continue following the subject until all unresolved system or procedure related AEs, as classified by the 
investigator, are resolved, unresolved with no further actions planned, or 30 days post follow up phone 
call. 
At the time of study exit, all collected adverse events that are unresolved must be reviewed and an update 
to the original AE must be reported.  
 
12.4. 
Definitions/Classifications 
Table 5: Adverse Event and Device Deficiency Definitions 
General 
Adverse Event (AE) 
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 and whether anticipated or 
unanticipated 
 
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. 
NOTE 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
(ISO 14155:2020, 3.2) 
Adverse Device Effect (ADE) 
AE related to the use of an investigational medical device 
 
NOTE 1: This definition includes AEs 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 an error use or from 
intentional misuse of the investigational medical device.  
NOTE 3: this includes ‘comparator’ if the comparator is a medical device. (ISO 
14155:2020, 3.1) 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
usability, safety or performance.  
 
NOTE 1: DD include malfunctions, use errors and inadequacy in the information 
supplied by the manufacturer including labeling.  

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NOTE2: This definition includes device deficiencies related to the investigational 
medical device or the comparator. (ISO 14155:2020, 3.19) 
Relatedness 
Procedure Related 
An AE that occurs due to any procedure. 
Seriousness 
Serious Adverse Event (SAE) 
 
AE that led to any of the following 
a) death, 
b) serious deterioration in the health of the subject, users or other persons as 
defined by one or more of the following:  
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, including 
chronic disease, or 
3) in-patient 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) fetal distress, fetal death or a congenital abnormality or birth defect including 
physical or mental impairment 
 
NOTE 1: Planned hospitalization for a pre-existing condition, or a procedure required by 
the CIP, without serious deterioration in health, is not considered an SAE. 
(ISO 14155:2020, 3.45) 
 
Serious Adverse Device Effect 
(SADE)  
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
(ISO 14155:2020, 3.44) 
 
 
12.5. 
Reporting of Adverse Events 
12.5.1 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 7 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: 

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Table 6: Adverse Event Classification Responsibilities 
What is classified?  
Who classifies? 
Classification Parameters 
Relatedness 
Investigator 
Device, Procedure   
Sponsor 
Device, Procedure 
Seriousness 
Investigator 
SAE, DD with SADE potential 
Sponsor 
SAE, UADE/USADE, Complication or Observation (for all system or 
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 
12.5.2 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.  
Table 7: Reporting Requirements  
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: 
 

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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 
 
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. 
 
Study Contact Information: 
Clinical Affairs 
Medical Affairs 

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Ami Stuart, PhD 
Clinical Study Manager  
Medtronic 
6135 Gunbarrel Avenue 
Boulder, CO 80301 
Phone: (801) 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 
 
12.6 Product Complaint Reporting 
Product complaint reporting and vigilance reporting are applicable and AEs related to any market-released 
device during the study must be reported. The reporting of product complaints is not part of the study 
and should be done in addition to the AE reporting requirements.  Refer to local regulations for reporting 
requirements.  
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. 
 
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic, regardless 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. The reporting of product complaints by the clinical team must be done according to the local 
Standard Operating Procedures. Medtronic will notify the RAs (e.g. CA) 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. 
• 
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: 
o Life-threatening illness or injury 
o Permanent impairment of a body function or permanent damage to a body structure 
o A condition necessitating medical or surgical intervention to prevent permanent impairment 
of a body function or permanent damage to a body structure 
13. Data Review Committees  
Neither a Data Monitoring Committee (DMC) nor an Adverse Events Advisory Committee (AEAC) will be 
utilized for this clinical study as there are no safety concerns suggesting the need for a DMC. This study is 
considered a non-significant risk for study participants. Thus, the need for additional safety oversight 

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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 
The 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 (CSR) 
Data exclusion will be captured in the Data Management Plan.    
 
 
14.1. 
Sample Size Justification 
A two-stage adaptive design is used in this study. For each regimen, 10 subjects will be enrolled in stage 
1, and upon evaluation, up to 20 additional subjects will be enrolled in stage 2. With 5 regimens, a 
maximum of 150 subjects will be expected. Based on the dose-response relationship (logistic model) with 
an allowable error of ± 15% for BIS50 and a coefficient of variation of 25% at the alpha level of 0.05, the 
sample size will provide sufficient power (>80%) to evaluate the performance of anesthetic agents.  
 
14.2. 
Analysis Populations 
All randomized subjects will be included in the analysis. For those subjects who do not complete a follow-
up call, the analysis will include all data up to the last collected point or follow-up call. Subjects who 
completed the procedure phase will not be replaced. If the subject discontinues prior to randomization 
or during the procedure phase, she/he will be replaced, but will count toward the total sample size if they 
were randomized. 
 
14.3. 
Statistical Methods 
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.  
 
Any subject who responds to any verbal command with MOAA/S assessment scores of 2, 3, 4, and 5 will 
be considered as responsive. Subjects with MOAA/S assessment scores of 0 and 1 will be considered 
unresponsive. Tetanic Electrical Stimulation (TES) will be employed with an MOAA/S assessment score of 
≤2 for the first two subjects in each group and <2 for all other subjects. 

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The BIS™ index value collected from the left side of the brain will be used for primary analysis to reflect 
the typical operation of the device from this study. The BIS™ index value collected from the right side of 
the brain will be used for internal research purposes.  
 
The logistic model (simplified Sigmoid Emax model) will be used to analyze the relationship between the 
BIS™ index and loss of responsiveness through the probability of response curves. The values of BIS™ at 
which 50% (BIS50) and 95% (BIS95) of subjects are unresponsive, and their 95% confidential intervals will 
be derived. The systematic variance between groups will be evaluated. The Prediction Probability score 
(Pk) for correctly predicting if the subject was responsive or unresponsive will be assessed.   
 
14.4. 
Interim Review 
The interim review will be performed at the end of stage 1, when all (50 subjects 10 subjects per regimen 
group) subjects have completed the evaluation. BIS™ values will be estimated using the Hill equation. One 
or more regimens may be dropped upon interim results for safety concerns (unacceptable safety events 
per clinical judgment).    
 
For the final analysis, data from stage 1 and stage 2 will be combined by further taking into account pool-
ability across sites and the adaptive nature of the 2-stage design (e.g., Bayesian integration with power 
prior and discounting function). Technical details will be specified in the SAP.   
15. Ethics 
 
15.1. 
Statement(s) of Compliance  
The investigator is responsible for ensuring that the clinical study is conducted in accordance with: 
• 
The Declaration of Helsinki (2013) and local laws and regulations of the countries in which the 
clinical study is conducted, including data protection laws, the Clinical Trial Agreement, Good 
Clinical Practice (GCP) E6 and regulatory requirement(s), including 21 CFR 803, 21 CFR 812.2, 21 
CFR 50, 21 CFR 56. FDA Financial Disclosure regulations, 21 CFR 54, and this Clinical Investigational 
Plan. 
• 
All principles of the Declaration of Helsinki have been implemented in this clinical study by means 
of the informed consent process, IRB approval, clinical study training. 
• 
Investigators must inform Medtronic of any change in the status of IRB approval once the 
investigation site has started 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 or regulatory authority (if applicable) approval/ 
notification is received. Written IRB approval and any conditions of approval imposed by the IRB 
must be submitted to the Sponsor.  

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• 
If the IRB or other regulatory authorities impose any additional requirements (e.g., safety reports, 
progress reports, etc.), Medtronic will prepare the required documents and send them to the 
respective authority. 
16. Study Administration 
 
16.1. 
Monitoring  
Site monitoring visits will be performed by the study monitor or other qualified sponsor staff per the 
monitoring plan onsite or remotely to ensure: 
• 
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. 
• 
Adverse events and protocol deviations are documented and reported. 
• 
Investigational and non-investigational device accountability and disposition are accurately 
documented.  
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. 
 
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.  
 
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.  

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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 the study sponsor and authorized 
sponsor’s representatives, 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 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. 
 
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 a CRF, 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 or remote access to subject medical files 
for source data verification will need to be granted and prepared prior to any monitoring visits.   
 

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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 or 
investigational device or investigational device use. 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 
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 

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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, RA and the investigator that pertains to 
the investigation, including required reports.  
• 
Subject’s case history records, including:  
o Signed and dated ICF  
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 
• 
Financial Disclosure (FD)  
• 
Subject screening log & ID log  
• 
Normal value(s)/range(s) for clinical laboratory test (if applicable) 
• 
Lab certificate 
• 
Device Disposition Logs containing Model and serial numbers of devices delivered to the  study 
site, subject IDs of the subjects implanted, received dates of devices, implant/used dates, explant 
dates, 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, ICF  
• 
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.  
• 
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.   
• 
Regulatory Authority (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.  

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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 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  
• 
All approved ICF 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, IB/Report of Prior Investigations summary and study related reports, 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.  
 
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 
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 

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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 
UADE 
Sponsor 
An investigator shall submit to the sponsor and to the reviewing IRB a report of 
any UADE occurring during an investigation as soon as possible, but in no event 
later than 10 working days after the investigator first learns of the effect. (21 CFR 
812.150(a)) 
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 12 months of study completion or 
termination. 
Sponsor Reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports (by geography).  
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.  
 
 
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 
before the first enrollment. 
 
While study results are owned by the Sponsor, all data on which a publication is based will be made 
available to all authors as required for their participation in the publication processes. Furthermore, 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. Investigators must submit a copy of all manuscripts and/or abstracts to the Sponsor for review 

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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. 
 
The number of authors will be dependent on the regulations of the concerning journal. Authorship on any 
publication(s) resulting from this clinical study will be assigned according to substantial contributions to 
conception and design, acquisition of data, or analysis and interpretation of data, drafting the article or 
revising it critically for relevant intellectual content and final approval of the version to be published. 
Names of all participating investigators will appear in the Acknowledgment of the paper.  
 
The publication of sub-studies, post-hoc analyses, regional results, or single-center experiences based on 
multicenter clinical studies should not precede that of the primary multicenter publication and should cite 
the primary publication whenever possible, as required by specific journal and scientific meeting 
guidelines. 
 
Medtronic involvement in a publication (e.g., funding of the study; sponsor of the study; collection, 
analysis, and interpretation of data; professional writing assistance) must be disclosed according to 
journal-specific policies, submission requirements, and prevailing editorial standards, in addition to those 
specified by International Committee of Medical Journal Editors. The authors must ensure that an 
acknowledgment/disclosure statement is included in the body of the manuscript for Medtronic to review 
for accuracy. All authors must also disclose financial or personal affiliations that could be considered 
conflicts of interest as per journal/conference requirements. 
 
Medtronic, as the owner of the data, can use the data and/or any results derived from the data or 
publications based on that data for marketing purposes, further research, and development of devices or 
educational use. The study sponsor will collect data in such a way that no subject can be identified and 
monitor study records. Participating subjects will not be identified by name in any published reports about 
the clinical study. 
 
16.10. Suspension or Early Termination 
The Sponsor reserves the right to discontinue the study at any stage, with written notice to all 
investigators, all reviewing IRBs. 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 

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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.) 
 
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: 
• 
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 
• 
Noncompliance 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) 
17. References 
1. 
Minto, C.F., T.W. Schnider, and S.L. Shafer, Pharmacokinetics and Pharmacodynamics of 
Remifentanil: II. Model Application. Anesthesiology 1997. 86: p. 24-33. 
2. 
Iwakiri, H., et al., Effect-Site Concentration of Propofol for Recovery of Consciousness Is Virtually 
Independent of Fentanyl Effect-Site Concentration. Anesth Analg, 2003. 96: p. 1651-5. 

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3. 
Alkire, M.T., A.G. Hudetz, and G. Tononi, Consciousness and Anesthesia. Science, 2008. 322: p. 
876-880. 
4. 
Rampil, I.J., A Primer for EEG Signal Processing in Anesthesia. Anesthesiology, 1998. 98(4): p. 
980-1002. 
5. 
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. 
6. 
Akeju, O., et al., Effects of Sevoflurane and Propofol on Frontal Electroencephalogram Power and 
Coherence. Anesthesiology, 2014. 121(5): p. 990-998. 
7. 
Secretariat, M.A., Bispectral index monitor: an evidence based analysis., O.H.T.A. Series, Editor. 
2004. 
8. 
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. 
9. 
Glass, P.S., et al., Bispectral Analysis Measures Sedation and Memory Effects of Propofol, 
Midazolam, Isoflurane, and Alfentanil in Healthy Volunteers. Anesthesiology, 1997. 86(4): p. 836-
847. 
10. 
Aho, A.J., et al., Comparison of Bispectral Index and Entropy values with electroencephalogram 
during surgical anaesthesia with sevoflurane. Br J Anaesth, 2015. 115(2): p. 258-66. 
11. 
Bresil, P., et al., Impact of bispectral index for monitoring propofol remifentanil anaesthesia. A 
randomised clinical trial. Acta Anaesthesiol Scand, 2013. 57(8): p. 978-87. 
12. 
Bresson, J., et al., A Randomized Controlled Trial Comparison of NeuroSENSE and Bispectral Brain 
Monitors During Propofol-Based Versus Sevoflurane-Based General Anesthesia. Anesth Analg, 
2015. 121(5): p. 1194-201. 
13. 
Brown, C.H.t., et al., Sedation depth during spinal anesthesia and survival in elderly patients 
undergoing hip fracture repair. Anesth Analg, 2014. 118(5): p. 977-80. 
14. 
Chan, M.T.V., et al., BIS-guided Anesthesia Decreases Postoperative Delirium and Cognitive 
Decline. J Neurosurg Anesthesiol, 2013. 25: p. 33-42. 
15. 
Cheung, Y.M., et al., Evaluation of the aepEX monitor of hypnotic depth in pediatric patients 
receiving propofol-remifentanil anesthesia. Paediatr Anaesth, 2013. 23(10): p. 891-7. 
16. 
Cheung, Y.M., et al., Evaluation of the auditory evoked potentials derived aepEX() as a measure 
of hypnotic depth in pediatric patients receiving sevoflurane-remifentanil anesthesia. Paediatr 
Anaesth, 2014. 24(7): p. 760-5. 
17. 
Conte, V., et al., Bispectral Index During Asleep-Awake Craniotomies. J Neurosurg Anesthesiol, 
2013(25): p. 279-284. 
18. 
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. 
19. 
Fritz, B.A., H.R. Maybrier, and M.S. Avidan, Intraoperative electroencephalogram suppression at 
lower volatile anaesthetic concentrations predicts postoperative delirium occurring in the 
intensive care unit. Br J Anaesth, 2018. 121(1): p. 241-248. 
20. 
Fritz, B.A., et al., ostoperative Recovery with Bispectral Index versus Anesthetic Concentration-
guided Protocols. ASA publications Anesthesiology 2013. 118(5): p. 1113. 
21. 
Jindal, A., et al., Bispectral index monitoring for diagnosis and assessment of severity of hepatic 
encephalopathy in cirrhotic patients. Dig Liver Dis, 2015. 47(9): p. 769-74. 

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22. 
Jung, J.Y., C.B. Cho, and B.M. Min, Bispectral index monitoring correlates with the level of 
consciousness in brain injured patients. Korean J Anesthesiol, 2013. 64(3): p. 246-50. 
23. 
Kertai, M.D., W.D. White, and T.J. Gan, Cumulative Duration of “Triple Low” State of Low Blood 
Pressure, Low Bispectral Index, and Low Minimum Alveolar Concentration of Volatile Anesthesia 
Is Not Associated with Increased Mortality. Anesthesiology, 2014(121): p. 18-28. 
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Lee, S.Y., et al., Comparison of bispectral index scores from the standard frontal sensor position 
with those from an alternative mandibular position. Korean J Anesthesiol, 2014. 66(4): p. 267-73. 
25. 
Liu, P.P., et al., The prediction probabilities for emergence from sevoflurane anesthesia in 
children: A comparison of the perfusion index and the bispectral index. Paediatr Anaesth, 2018. 
28(3): p. 281-286. 
26. 
Mei, B., et al., Peripheral Nerve Block as a Supplement to Light or Deep General Anesthesia in 
Elderly Patients Receiving Total Hip Arthroplasty: A Prospective Randomized Study. Clin J Pain, 
2017. 33(12): p. 1053-1059. 
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Nitzschke, R., et al., Bispectral index guided titration of sevoflurane in on-pump cardiac surgery 
reduces plasma sevoflurane concentration and vasopressor requirements: a prospective, 
controlled, sequential two-arm clinical study. Eur J Anaesthesiol, 2014. 31(9): p. 482-90. 
28. 
Orliaguet, G.A., et al., Feasibility of Closed-loop Titration of Propofol and Remifentanil Guided by 
the Bispectral Monitor in Pediatric and Adolescent Patients. Anesthesiology. 122: p. 759-767. 
29. 
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31. 
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18. Appendices  
Appendix A - Modified Observer's Assessment of Alertness/Sedation scale  
 
The Observer Assessment of Alertness/Sedation (OAA/S) Scale [47] 
Response  
Score 
Responds readily to name spoken in normal tone 
5 
Responds lethargically to name spoken in normal tone 
4 
Responds only after name is called loudly, repeatedly, or both 
3 
Responds only after mild prodding or shaking 
2 
Responds only after painful trapezius squeeze 
1 

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Does not respond to painful trapezius squeeze 
0 
 
Appendix B – Open Affective Standardized Image Set (OASIS) 
 
Pictures attached as zip file due to size. 
 
Appendix C – NCM Sub-Study – Non-Contact Depth-Sensing Respiratory Monitoring  
All subjects enrolled in MDT19053OLIVER Study (Main Study) may be invited to participate in the product 
development sub-part of the study. The purpose of this non-contact monitoring sub-study (NCM Sub-
Study) is to collect data for further exploration of a non-contact physiological monitoring system based 
on depth-sensing camera technology.  
 
Medtronic is continuously improving its monitoring devices to improve performance and widen the range 
of capabilities. In order to develop and assess a newly developed technology, the NCM Sub-Study is 
executed to collect data to show early feasibility and proof of concept for novel non-contact monitoring 
technology. 
 
Background 
Recently, Medtronic has worked on depth-sensing technologies where the distance from the camera to 
objects within the field of view is captured and used to produce physiological information, including 
airway resistance, heart rate, respiratory rate, volume change, and apnea events. Depth sensing cameras 
produce grayscale images where the intensity of pixels corresponds to the distance from the camera. 
Color mapping can be used to create false color images where the colors correspond to the distance from 
the camera, an example of which is contained in Figure 5. 
 

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Figure 5: A false color depth image where a subject can be identified. A light blue mask indicates the torso region of interest 
(ROI) from where the volume change signal is computed. The volume change signal is shown in the lower part of the figure. 
 
From this image, we have developed a technology to automatically superimpose a mask on the torso of 
the subject (as shown in Figure 5) from which we can measure distances from the camera over time. By 
integrating the change in the distance on the torso region of interest (ROI) over time, we can provide a 
real-time estimate of tidal volume change as the lungs expand and contract during inhalation and 
exhalation, respectively. An example of this calculated volume change signal is shown at the bottom of 
Figure 5. The volume change signal can then be converted to a tidal volume per breath and a respiratory 
rate (and hence minute volume). 
 
From the volume change signal, we can extract a variety of physiological parameters, including tidal 
volume (peak-to-trough amplitude of the volume change signal), respiratory rate (frequency of volume 
change signal modulations), individual breath period and corresponding inhalation/exhalation (I/E) ratio, 
minute volume, etc. We can also extract a volume change signal from the chest and abdomen regions 
separately from which an indication of out of phase breathing, indicative of obstructive apnea, can be 
derived (as shown in Figure 6). The technology also detects cessation of breathing, talking, and coughing.  

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Figure 6: Paradoxical breathing shown on a subject’s torso. Green indicates regions where the subject torso is moving 
towards the camera. Red indicates regions where the subject torso is moving away from the camera. Yellow/black indicates 
non-moving regions.  
 
Objective 
To collect depth-sensing video and respiration waveform signal data to explore the feasibility of non-
contact respiratory monitoring technology.  
 
 
 
Product Description  
The RealSense D415 depth camera system (manufactured by INTEL™) is a non-contact camera technology 
for determining distances of objects in a scene using infrared sensing technology. It is a consumer product 
developed by INTEL™. Other commercially available depth-sensing systems may be employed in the study, 
(for example, the Microsoft™ Kinect Azure or Microsoft™ Kinect V2, INTEL RealSense D435, INTEL™ 
RealSense L515, Stereolabs™ ZED depth-sensing cameras or similar). Cameras may be used off-the-shelf, 
and no modifications to the actual product are required.  
 
Study Visit (Main Study Visit 2) 
For the subject who enrolled in the main study and consented to participate in NCM Sub-Study:  
• 
Non-contact monitoring (NCM) camera will be placed 1.0 – 2.5 m from the subject (on a tripod or 
attached to the trolley, etc.) prior to the administration of any drugs and assessment for the Main 
Study.  
• 
Make sure the subject is in view of the NCM camera and start recording.  
• 
If non-contact monitoring equipment malfunctions, the Main Study will continue without 
stopping or interference from the NCM sub-part.  
• 
Exact placement and distance of the cameras should be documented on the paper CRF.  

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• 
Raw non-contact monitoring data will be provided to Medtronic. 
 
Analysis  
The collected data from a pulse oximeter, capnography, and depth-sensing camera equipment will be 
used to develop a real-time non-contact respiratory monitoring system. Data will be analyzed and post-
processed for this purpose. Additional analysis may be performed as necessary. 
 
 
 

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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, BS, CCRC 
Sr. Clinical Research Specialist 
2.0 
• 
Addition of Picture Recall Test 
• 
Changed TES assessment from one 
stimulation to 4 graduated stimulations 
• 
Added UADE reporting requirements to 
address GAP identified in versioning 
• 
Clarification 
of 
Adverse 
Events 
collection time period 
• 
Clarification 
of 
Anesthesiologists 
permitted 
to 
perform 
MOAA/S 
assessment 
 
Stephanie Monza, BS, CCRC 
Sr. Clinical Research Specialist 
3.0 
• 
Change of procedure to increase 
anesthesia until a BIS™ value of 30 is 
reach or per Investigator’s discretion 
• 
Clarification of Statistical Plan 
• 
Pictures used in Picture Recall Test 
changed to OASIS 
Stephanie Monza, BS, CCRC 
Sr. Clinical Research Specialist 
4.0 
• 
Clarification 
of 
Picture 
Recall 
Assessment 
• 
Change of Anesthesia amounts to align 
to anesthesia device delivery amounts 
• 
Additional step of sevoflurane due to 
incidence of hypotension 
• 
Addition of use of lidocaine to decrease 
discomfort to subjects 
• 
Change of timing of TES assessment to 
ensure adequate sedation 
• 
Addition of phenylephrine to prevent 
hypotension 
• 
Addition of NCM sub-study 
Stephanie Monza, BS, CCRC 
Sr. Clinical Research Specialist 
5.0 
• 
Change 
in 
administration 
of 
phenylephrine 
to 
be 
at 
the 
investigator’s discretion 
Ami Stuart, PhD, MSCI 
Sr. Clinical Research Specialist 

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• 
Addition of ondansetron to prevent 
emesis / nausea administered at the 
investigator’s discretion  
• 
Update of contact information for 
Clinical Affairs