A Randomised Controlled Trial to Reduce Postoperative Delirium Through Reduction in Intraoperative EEG Suppression in Older Surgical Patients Undergoing Major Noncardiac Surgery
Phase: NA
Conditions: Delirium, Cognitive Disorders
Sponsor: University of California, San Francisco

ADAPT-2 (Anesthetic Depth and Postoperative Delirium Trial – 2) 
 
 A randomized controlled trial to reduce postoperative delirium through reduction 
in intraoperative EEG suppression in older surgical patients undergoing major 
noncardiac surgery 
 
 
Clinical trial number and registry URL: NCT01983384 
 
 
 
Version date: July 25, 2018 
 
 
 
 
Principal Investigator: 
Jacqueline M Leung, MD, MPH 
Professor & Vice Chair of Academic Affairs 
UCSF Department of Anesthesia & Perioperative Care 
500 Parnassus Avenue, Room MUE-415 
San Francisco, CA 94143-0648 
Phone: 415-476-0711 
Email: Jacqueline.Leung@ucsf.edu  
 
 

Study Application (Version 1.7)
1.0
General Information
*Enter the full title of your study:
The Effect of Anesthetic Depth on Postoperative Cognitive Outcomes, II
 
 
*Enter the study number or study alias
ADAPT 2
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this 
study.
 
 
2.0
Add Department(s)
2.1 List departments and/or research programs associated with this study:
Primary 
Dept?
Department Name
UCSF - 
 - M_Anesthesia
127037
UCSF - 
 - M_Laboratory Medicine
144075
 
3.0
Assign key study personnel(KSP) access to the study
3.1 *Please add a Principal Investigator for the study:
 
Leung, Jacqueline M, MD, MPH
Select if applicable
Department Chair
Resident
Fellow
If the Principal Investigator is a Fellow, the name of the Faculty Advisor must be supplied below.
 
3.2 If applicable, please select the Research Staff personnel:
 
A) Additional Investigators
Kramer, Joel, PsyD 
 Other Investigator
Lieberman, Jeremy A 
 Other Investigator
B) Research Support Staff
Tang, Christopher J 
 Research Assistant
l

3.3 *Please add a Study Contact:
 
Leung, Jacqueline M, MD, MPH 
Tang, Christopher J 
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal 
Investigator themselves).
3.4 If applicable, please add a Faculty Advisor/Mentor:
 
3.5 If applicable, please select the Designated Department Approval(s):
 
Gropper, Michael Allan, MD, PhD 
Department Chair
Add the name of the individual authorized to approve and sign off on this protocol from your 
Department (e.g. the Department Chair or Dean).
4.0
 Qualifications of Key Study Personnel
4.1  November, 2015 - NEW Definition of Key Study Personnel and CITI Training 
Requirements:    
  
include the Principal Investigator, other investigators and research 
UCSF Key Study Personnel 
personnel who are directly involved in conducting research with study participants or who are directly 
involved in using study participants’ identifiable private information during the course of the 
research. Key Personnel also include faculty mentors/advisors who provide direct oversight to 
        
Postdoctoral Fellows, Residents and Clinical Fellows serving as PI on the IRB application.
 
The 
IRB requires that all Key Study Personnel complete Human Subjects Protection 
Training through CITI prior to approval of a new study, or a modification in 
which KSP are being added. More information on the CITI training requirement 
can be found on our website.
    
   
List the study responsibilities and qualifications of any individuals who qualify as Key Study 
 (KSP) at UCSF and affiliated sites ONLY by clicking the "Add a new row" button. 
Personnel
This 
 
information is required and your application will be considered incomplete without it.
KSP Name
Description of Study 
Responsibilities
Qualifications
Dr. Leung, Jacqueline M, MD, 
MPH
Dr. Leung will be the principal 
investigator and will design 
and oversee all aspects of the 
project and coordinate all the 
research activities. Dr. Leung 
will direct all pre-, intra-, and 
post-operative data collection 
and analysis. This will include 
all in-hospital and post-
discharge outcome data.
Dr. Leung is Professor of 
Anesthesia & Perioperative 
Care at the University of 
California, San Francisco 
(UCSF). Dr. Leung has 
extensive experience in 
designing and conducting 
clinical trials and outcomes 
research studies. Her earlier 
work has focused on areas 
relating to the importance, 
detection and therapy of 
perioperative myocardial 
ischemia in surgical patients 
with heart disease, as well as 
the cardiovascular effects and 
safety of anesthetics in high-
risk surgical patients. After 
devoting a full sabbatical year 

in 1997-1998 to obtain 
additional training in 
epidemiology and biostatistics, 
which resulted in a Master's 
degree in Public Health, Dr. 
Leung now focuses on 
outcomes research in the 
geriatric surgical patients. Dr. 
Leung leads a research team, 
the Perioperative Medicine 
Research Group, which 
consists of postdoctoral 
research fellows, research 
associates and students, 
based at UCSF.
Dr. Kramer, Joel PsyD
Dr. Kramer will help in the 
study design, particularly in 
the selection of 
neuropsychologic tests to be 
used for the study, and will 
also consult on all issues 
relating to neuropsychological 
testing of the subjects.
Dr. Kramer is a Clinical 
Professor of Neuropsychology 
and Neurology and the 
Director of the Memory and 
Aging Center Neuropsychology 
program at UCSF. Dr. Kramer 
has been extensively involved 
in studying the cognitive 
changes associated with brain 
disorders for the past two 
decades. He has co-authored 
widely used 
neuropsychological measures 
of memory and executive 
functioning. Much of his work 
has been devoted to 
identifying the different ways 
in which neurodegenerative 
diseases affect memory and 
other abilities and in utilizing 
these differences to improve 
differential diagnosis of 
cognitive disorders.
Lieberman, Jeremy A
Dr. Lieberman will assist with 
monitoring the anesthetic 
depth of patients.
Dr. Lieberman is a Clinical 
Professor of Anesthesia and 
Perioperative Care at UCSF.
Shalabi, Ahmed M
Dr. Shalabi will assist with 
monitoring the anesthetic 
depth of patients.
Dr. Shalabi is an Assistant 
Clinical Professor of 
Anesthesia and Perioperative 
Care at UCSF.
Tang, Christopher J
Mr. Christopher Tang will 
assist with the recruitment of 
surgical patients and with 
preoperative and longterm 
cognitive testing.
Mr. Temur Kamal is a research 
associate working under Dr. 
Leung. He has extensive 
experience with clinical trials 
analysis for the project and 
outcome studies, specifically 
investigating the 
pathophysiology of 
postoperative delirium and 
cognitive dysfunction in older 
surgical patients.
5.0
 Initial Screening Questions - Updated 9/13
(Note: You must answer every question on this page to proceed).

If you are converting to the new form, check questions 5.4, 5.6, 5.7, 5.8 
and 5.10 before saving and continuing to the next section.
5.1  
 Application type:
*
Full Committee 
Expedited 
Exempt 
5.2  
 Risk level 
:
*
(Help Text updated 9/13)
Minimal risk 
Greater than minimal risk 
5.3  
 Subject contact:
*
Yes (including phone, email or web contact) 
No (limited to medical records review, biological specimen analysis, and/or data analysis) 
5.4  
 Funding (past or present):
*
Funded or will be funded (external sponsor, gift, program or specific internal or departmental funds) 
Unfunded (no specific funds earmarked for this project) 
Unfunded student project 
5.5  
The Principal Investigator and/or one or more of the key study personnel has 
 
* 
financial interests
related to this study:
  Yes   
  No
If 
, the Conflict of Interest Advisory Committee (COIAC) office may contact you for additional 
Yes
information.
5.6  
This is an investigator-initiated study:
* 
 Yes   
 No
5.7  
This study 
 involves retrospective records review and/or identifiable biospecimen analysis:
* 
ONLY
  Yes   
  No
5.8  
This is a clinical trial:
* 
 Yes   
 No
Clinical Trial Registration
"NCT" number for this trial:
NCT01983384
5.9  * This is a multicenter study:

  Yes   
  No
5.10  
This application involves the study of 
 or 
 drugs, devices, biologics or in vitro 
* 
unapproved
approved
diagnostics:
 Yes   
 No
5.11  * This application involves a Humanitarian Use Device:
No 
Yes, and it includes a research component 
Yes, and it involves clinical care ONLY 
5.12  
This study involves human stem cells (including iPS cells and adult stem cells), gametes or 
* 
embryos:
No 
Yes, and requires CHR and GESCR review 
Yes, and requires GESCR review, but NOT CHR review 
5.13  * This is a CIRB study (e.g. the NCI CIRB will be the IRB of record):
  Yes   
  No
5.14  
This application includes a request to rely on another IRB (other than NCI CIRB):
* 
  Yes   
  No
Note: If this request is approved, the CHR will 
 review and approve this study. Another institution will 
NOT
be the IRB of record.
6.0
 Funding
6.1  Identify all sponsors and provide the funding details. If funding comes from a Subcontract, please list 
only the Prime Sponsor:        
 
Note: we require only a P Number 
 an A Number for 
OR
funding coming through UCSF. Please avoid these common errors in funding 
       
documentation: 
 
 
DO NOT add the A Number if a P Number was already provided OR update 
the A Number field when a new funding cycle begins. The IRB does NOT 
use this information or want these changes made.   
 add a grant continuation as a new funding source. 
DO NOT
External Sponsor:
View 
Details
Sponsor Name
Sponsor Type
Awardee 
Institution
Contract 
Type:
UCSF RAS 
"P 
number" 
or 
eProposal 
number 
UCSF 
RAS 
System 
Award 
Number 
("A" + 
6 
digits) 

NIH Center for 
Scientific Review 
01 
UCSF 
Grant 
P0502184  
Sponsor Name:
NIH Center for Scientific Review 
Sponsor Type:
01 
Sponsor Role:
Funding
Grant/Contract Number:
1R21AG048456-01A1 
Awardee Institution:
UCSF 
Is Institution the Primary Grant 
Holder:
Yes 
Contract Type:
Grant 
UCSF RAS "P number" or 
eProposal number:
P0502184 
UCSF RAS System Award Number 
("A" + 6 digits):
 
Grant Number for Studies Not 
Funded thru UCSF:
 
Grant Title:
The Effects of Light vs. Deep Anesthesia on Postoperative 
Cognitive Outcomes 
PI Name:
(If PI is not the same as identified 
on the study.)
 
Significant Discrepancy:
 
Gift, Program, or Internal Funding (check all that apply):
Funded by gift (specify source below)
Funded by UCSF or UC-wide program (specify source below)
Specific departmental funding (specify source below, if applicable)
List the gift, program, or departmental funding source:
6.2    
   
If you tried to add a sponsor in the question above and it was not in the list, follow these steps:
If funding has already been awarded or the contract is being processed by the Office of 
Sponsored Research (OSR) or Industry Contracts Division (ICD), your sponsor is already in the 
system and the project has an eProposal Proposal or Award number. Check with your 
department's OSR Staff or ICD Officer to ask how the sponsor is listed in the UC sponsor list 
and what the Proposal or Award number is. Click 
 to find your OSR staff and 
 to find 
here
here
your ICD staff.
If your sponsor is not yet in the list, enter it in the box below.
Sponsor not in list 
Only if your sponsor is not yet in the list, type the sponsor's name:
If the funding is administered by the UCSF Office of Sponsored Research, your study will not 
receive CHR approval until the sponsor and funding details have been added to your 
application.
6.3  
This study is currently supported in whole or in part by Federal funding OR has received ANY 
* 
Federal funding in the past 
:
(Help Text updated 9/13)

 Yes   
 No
If 
, indicate which portion of your grant you will be attaching:
yes
The Research Plan, including the Human Subjects Section of your NIH grant or subcontract
For other federal proposals (contracts or grants), the section of the proposal describing human 
subjects work
The section of your progress report if it provides the most current information about your human 
subjects work
The grant is not attached. The study is funded by an award that does not describe specific plans for 
human subjects, such as career development awards (K awards), cooperative agreements, program 
projects, and training grants (T32 awards) OR UCSF (or the affiliate institution) is not the prime 
recipient of the award
7.0
 Sites
7.1  Institutions (check all that apply):
UCSF
China Basin
Helen Diller Family Comprehensive Cancer Center
Mission Bay
Mount Zion
San Francisco General Hospital (SFGH)
SF VA Medical Center (SF VAMC)
Blood Centers of the Pacific (BCP)
Blood Systems Research Institute (BSRI)
Fresno (Community Medical Center)
Gallo
Gladstone
Institute on Aging (IOA)
Jewish Home
SF Dept of Public Health (DPH)
7.2  Check all the other types of sites not affiliated with UCSF with which you are cooperating or 
collaborating on this project 
:
(Help Text updated 9/13)
Other UC Campus
Other institution
Other community-based site
Foreign Country
List the foreign country/ies:
7.3  Check any research programs this study is associated with:
Cancer Center
Center for AIDS Prevention Sciences (CAPS)
Global Health Sciences
Immune Tolerance Network (ITN)
Neurosciences Clinical Research Unit (NCRU)
Osher Center
Positive Health Program

8.0
 Studies Involving Other Sites
8.1  UCSF is the coordinating center:
  Yes   
  No
If 
, describe the plan for communicating safety updates, interim results, and other information that 
Yes
may impact risks to the subject or others among sites:
If 
, describe the plan for sharing modification(s) to the protocol or consent document(s) among sites:
Yes
8.2  Check any other UC campuses with which you are collaborating on this research study:
UC Berkeley
UC Davis
Lawrence Berkeley National Laboratory (LBNL)
UC Irvine
UC Los Angeles
UC Merced
UC Riverside
UC San Diego
UC Santa Barbara
UC Santa Cruz
8.3  Are the above UC campuses requesting to rely on UCSF's IRB (check all that apply):
Yes (Submit a reliance request through the UC IRB Reliance Registry)
No (Complete IRB Approval Certification section)
9.0
 Outside Site Information
9.1  
 
Outside Site Information
Click "Add a new row" to enter information for a site. Click it again to add a second site again to add a 
third site, a fourth site, etc.
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Virginia Polytechnic Institute and State University
Contact name:
Laura Sands
Email:

lsands@vt.edu
Phone:
514-231-6074
For Federally-funded studies only, corresponding FWA#:
 research at this site will be reviewed by:
* The
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this study 
The non-affiliated site is not engaged in the human subjects research and has 
provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the 
application.  If the IRB approval letter is not yet available, submit it once you 
receive it. 
  
  Or, if the other site is 
 in human subjects research, attach the 
 
not engaged
letter of support to your application.
10.0
 Study Design
10.1  
Study design 
:
* 
(Help Text updated 9/13)
The proposed study will include a randomized control trial of 204 older patients undergoing major non-
cardiac surgery, who will be randomized to receive processed EEG-guided anesthetic levels during surgery 
vs. standard care. Assessments will include the 1) measurement of anesthetic depth, measured before and 
during surgery using an approved anesthetic depth monitor (SEDline), 2) measurement of cognitive 
status, cognitive function measured pre- and post- operatively while the patients are in the hospital using 
the Digit Symbol, Word list, Verbal fluency, and Digit Span and also at one month and three months 
postoperatively by phone using the neurocognitive test  described in the our previously approved studies, 
s
this includes the Telephone Interview for Cognitive Status (TICS). Based on studying over one thousand 
patients, we estimate that it will take 10 minutes for the one month and three month follow-up calls, and 
3) screening of delirium using the Confusion Asssessment Method Rating Scale (CAM). The outside 
collaborator, Dr. Sands from Virginia Polytechnic Institute and State University, will help with data 
analysis, but will not have access to subject identifiers.
10.2  If this is a clinical trial, check the applicable phase(s) 
:
(Help Text updated 9/13)
Phase I
Phase II
Phase III
Phase IV
11.0
 Scientific Considerations
11.1  Hypothesis 
:
(Help Text updated 9/13)
This study has a hypothesis:

 Yes   
 No
If yes, state the hypothesis or hypotheses:
Preoperative level of cognitive function moderates the effect of anesthetic depth on incident delirium or 
POCD.
 
11.2  
List the specific aims:
* 
The specific aims of this randomized control trial are:
1.     To determine the feasibility and safety of randomizing patients undergoing major non-cardiac surgery 
to receive processed EEG-guided anesthetic levels during surgery vs. standard care.  In this exploratory 
study, we aim to determine whether processed EEG guided anesthetic management can be practiced 
uniformly by a number of anesthesia providers across a large group of older surgical patients.
2.     To determine an effect size for designing a future larger trial to determine whether anesthetic depth 
contributes to an increased incidence of adverse postoperative cognitive outcomes as measured by 
delirium or cognitive decline.
3.     To determine whether preoperative level of cognitive function moderates the effect of depth of 
anesthesia on incident delirium or POCD.
 
11.3  Statistical analysis: 
We will use descriptive statistics to describe the characteristics of the study sample and to compare 
baseline characteristics in the two treatment groups.  We will use two-sample t tests, Mann-Whitney 
nonparametric tests, chi-square tests, or contingency table tests to compare the demographic and clinical 
characteristics between the interventional and standard care groups.  These analyses serve to validate that 
randomization was effective.  If any characteristics are significantly unbalanced, we will conduct 
multivariate analyses to adjust for such variables.  We will use an intention to treat paradigm in assessing 
the effect of anesthetic depth on the development of delirium and POCD.
Aim 1.  We will test whether assignment to EEG-guided anesthetic management will result in significant 
differences in PSI scores.  Prior to model construction, the total time that the PSI is in the range specified 
by the protocol in the interventional group will be plotted and transformations will be performed as 
necessary to meet model assumptions.  We will compute a mixed effects model to treat group membership 
as a fixed effect, the anesthesiologist as the random effect, and the total time that the PSI is in range as 
the dependent variable.  This model will include any patient characteristics known to differ between 
treatment groups at baseline.  When considering the impact of group assignment on autonomic signs, we 
will construct a variety of models in which the dependent variables are operationalized using a variety of 
methods including clinically relevant thresholds and variability over time as described in our earlier 
published work.  Again, we will use mixed models as specified above and the distribution associated with 
the model will depend upon the distributional characteristics of the dependent variable under study.  We 
will determine whether the groups differ in risk for use of vasoactive drugs using mixed a logistic 
regression model in which anesthesiologist is treated as a random effect, treatment group as a fixed effect 
and patient characteristics that differ at baseline will be included as covariates.  A mixed effect regression 
model will be used to determine whether quantity of vasoactive agents differ between groups (using 
appropriate transformations on the dependent variable).  Descriptive statistics of anesthesiologist 
responses to questions about why they could not adhere to the assigned threshold will be calculated for 
each group.
Aim 2.  To test whether assignment to EEG-guided anesthetic depth management affects postoperative 
cognitive outcomes.  The first analysis will use an intention to treat paradigm to determine the effect sizes 
associated with assignment to the interventional vs. the standard care groups.  Chi-square analyses will be 
conducted to determine the association between group assignment and incident delirium and incident 
POCD.  We will then create PSI categories based on the amount of time the patient was in the prescribed 
range of PSI (the category cut-offs will be informed both by the distribution of times and clinical 
relevance).  We will determine the association between these PSI categories and incidence of delirium and 
POCD separately using mixed logistic models with the physician as a random effect.  We will also compute 
longitudinal mixed models in which the dependent variables are the postoperative assessments of delirium 
severity (using the MDAS) and cognitive function (Word List, Verbal Fluency, Digit Symbol, and Digit Span 
scores) to determine the association between PSI categories and change in cognition over time.
Aim 3.  To determine whether preoperative level of cognitive impairment moderates the effect of EEG-
guided anesthesia on incident delirium or POCD.  We will construct hierarchical linear models to predict 
incident delirium or POCD.  Those models will include anesthesiologist as a random effect and group 
membership, preoperative level of cognitive impairment (as defined by the preoperative cognitive test 
scores) and the interaction between level of cognitive impairment and group membership to determine 
whether the association between group membership and incident delirium is moderated by preoperative 
cognitive impairment.  We will conduct a similar model using total time in the specified PSI range to 

measure the extent to which baseline cognitive functioning moderates the association between group 
assignment and PSI levels.
11.4  If this study has undergone scientific or scholarly review, please indicate which entity performed the 
review:
Cancer Center Protocol Review Committee (PRC) (Full approval is required prior to final CHR approval 
for cancer-related protocols.)
CTSI Clinical Research Center (CRC) advisory committee
Departmental scientific review
Other:
Specify 
:
Other
NIH: Surgery, Anesthesiology & Trauma (SAT) Study Section
12.0
 Background
12.1  Background:
     Because of increasing life expectancy and improved anesthesia and surgical techniques in the US, more 
surgical procedures are being performed on the very old.  The older population has the highest rate of 
surgical procedures.  Although many older patients have good perioperative outcomes, postoperative 
cognitive changes, in particular postoperative delirium, remains one of the most prevalent consequences of 
surgery.  Delirium is an acute confusional state with alterations in attention and consciousness (1), 
occurring in 10% to 60% of patients after major surgery, with associated mortality rates of 10%-65% (2, 
3).  In contrast, postoperative cognitive decline (POCD) refers to declines in cognitive functioning that can 
occur in the absence of delirium, and reported to occur in 7-26% of patients (4-7).  POCD has also been 
associated with impairments in daily functioning (8), premature departure from the labor market (9), and 
dependency on government economic assistance after hospital discharge (9).
     The development of delirium is thought to be a multifactorial process in which there is a complex 
interrelationship between baseline patient vulnerability and precipitating factors or insults (10).  In surgical 
patients, predisposing risk factors for delirium include age, pre-existent cognitive impairment, and pain, 
etc. (11, 12).  Precipitating factors include events related to surgery such as type of surgery, blood loss, 
exposure to medications with effects on the central nervous system such as opioids, and sleep disruption, 
etc. (11-14).
     Recently, it has been proposed that deep anesthetic depth contributes to an increased rate of 
postoperative delirium and POCD.  In a study of patients undergoing hip fracture repair receiving a spinal 
anesthetic, the use of light propofol sedation decreased the prevalence of postoperative delirium by 50% 
compared with deep sedation (15).  A more recent larger study in older patients undergoing non-cardiac 
surgery reported that intraoperative monitoring with a processed electroencephalogram (EEG) – Bispectral 
index (BIS), resulted in a reduced rate of postoperative delirium.  The investigators further showed that by 
multivariate analysis, deep anesthesia was independently predictive of postoperative delirium (16), but not 
POCD.  In contrast, other similar studies, which utilized the BIS monitor, did not show that low BIS levels 
were associated with early POCD.  For example the study by Chan et al., reported that BIS-guided 
anesthesia reduced anesthetic exposure and decreased the risk of POCD at 3 months after surgery but not 
at one week after surgery (17).  This result is curious because if anesthetics were to exert a “toxic” effect 
on the brain, one would expect to see POCD occurring immediately after surgery and not only at three 
months after surgery.  Two additional smaller studies in fact showed contradictory results, reporting that 
deeper levels of anesthesia were associated with better postoperative cognitive status (18, 19).  Of critical 
importance is that no previous study had determined the mechanism as to how deep levels of sedation or 
anesthesia result in postoperative delirium or cognition.  As a result, current data on whether deep 
anesthesia is harmful to the brain are inconclusive.
     Furthermore, previous studies addressing anesthetic depth and cognitive outcomes did not consider 
preoperative cognitive status as a potential moderator for the effects of anesthetic depth on postoperative 
cognitive outcomes.  Specifically, one of the most important baseline patient related factors contributing to 
adverse postoperative cognitive outcomes is pre-existing cognitive impairment.  Studies in patients with 
Alzheimer’s disease and mild cognitive impairment noted that abnormalities of resting state cortical EEG 
rhythms were not epiphenomena but were related to atrophy of cortical gray matter and cognition 
(20).  Therefore, a numerical value presented on BIS may simply represent a marker of some pre-existent 
decreased brain or cognitive function, independent of the exposure to anesthetics.  Alternatively, the depth 
of anesthesia may also be a marker for patient’s baseline brain vulnerability to the effects of anesthetics.
     Recently, some in the anesthesia field advocate that older patients should be routinely monitored by 
anesthetic depth monitor to avoid deep levels of anesthesia and its potentially adverse effects on 

postoperative cognition.  The implication that anesthetic is potentially toxic raises a public health concern 
that has not been thoroughly validated.  In fact, population studies suggest otherwise.  An exposure to 
general anesthesia, including frequency and duration of exposure was not predictive of cognitive 
performance (21).  In another study by Avidan et al., the trajectory of cognitive decline on long-term 
follow up was not affected by prior exposure to an anesthetic (22).  Finally, a meta-analysis on the effect 
of general anesthesia and regional anesthesia on postoperative delirium and POCD also concluded that 
there was no effect of anesthesia on these two outcomes (23), but this analysis did not consider the 
effects of anesthetic depth.  Taken together, it is timely and critically important to design a study to 
evaluate the effects of anesthetic depth on cognitive outcomes with proper consideration of patients’ 
baseline cognitive status, and other potential precipitating factors which have been demonstrated in 
previous studies to be independent factors for postoperative delirium and cognitive decline.  Some of these 
precipitating factors include intraoperative blood transfusion which may incite an inflammatory response 
(24), intraoperative blood pressure changes (25), and postoperative pain and opioids use, etc. (26).
            Accordingly, we aim to determine the feasibility and safety of conducting a randomized control 
trial with the ultimate goal to measure whether anesthetic depth during surgery contributes to an 
increased incidence of adverse postoperative cognitive outcomes as measured by delirium or cognitive 
decline, adjusted for preoperative cognitive function, and other known risk factors.  
 
12.2  Preliminary studies:
The principal investigator has been involved in outcomes research in the older hospitalized patients for over 20 
years.  Our recent work focuses on understanding the pathophysiology and significance of postoperative 
delirium.  The preliminary studies that are relevant to the aims proposed include:
Burst suppression and postoperative delirium - In a recent pilot study we just conducted (Anesthetic Depth and 
Postoperative Delirium Trial, 12-12510), we have enrolled 51 patients who underwent non-cardiac surgery at 
UCSF  (May 2
, 2014 to December 16 , 2014).  All patients were monitored with the Sedline brain monitor and 
nd
th
postoperative delirium and cognitive status were evaluated. All the raw EEG waveforms were analyzed by two 
neurologists who were blinded to patient demographics, anesthesia and cognitive outcome data. The Patient 
State Index (PSI), a continuous processed EEG number which represents anesthetic depth was also 
continuously recorded.
 
The major preliminary findings in this pilot study are:
1.  Delirium is significantly associated with longer time and larger percent of burst suppression
2.  Burst suppression seen on the raw EEG is typically associated with low PSI values (median PSI about 
15)
3.  Most anesthetized subjects who had no burst suppression have a median PSI value of about 35
 
 - We performed a pilot study of 24 
Use of a sedation monitor – SEDline brain monitor in older patients
olde
patients to determine the feasibility of the SEDline brain monitor in monitoring sedation level.  In all 
r 
enrolled subjects, we were able to continuously monitor their EEG and retrieve the raw EEG for review and 
analysis.  The SEDline monitor records not only the sedation level by way of a patient state index (PSI) but 
also provides 4 channel of raw EEG.  As illustrated in figure 1a where the SEDline monitor was applied in 
one patient who received intravenous sedation, the sedation level as measured by the PSI (green color) 
fluctuated from high (90) which indicates awake, to deep (50 or below).  In contrast, in a second patient 
(figure 1b) who did not receive sedation initially, the PSI remained relatively unchanged illustrating an 
awake state.
 
 – We have 
The importance of including preoperative patient vulnerability factor in delirium studies
conducted several cohort studies to examine the impact of possible preoperative patient vulnerability 
factors in influencing postoperative delirium.  We identified that preoperative symptoms of depression 
(27), preoperative physical frailty (28), and preoperative cognitive status (26) have independent effects on 
affecting risk of postoperative delirium.  These previous studies have provided us with an evidence-based 
approach to include appropriate variables that may modify the effects of anesthetic depth on postoperative 
delirium and POCD.
 
 – In 581 patients who were prospectively followed for the 
Consideration of moderators in risk modeling
development of postoperative delirium (26), we first developed a prediction model to determine which 
patients were at high vs. low risk for the development of delirium based on preoperative risk factors 
including co-morbidities.  We then modeled whether preoperative risk for delirium moderates the effect of 
postoperative pain and opioids on incident delirium.  Compared to patients at low preoperative risk for 
developing delirium, the relative risk for postoperative delirium in the high preoperative risk group was 
2.38 (95% CI = 1.67-3.40).  A significant three-way interaction indicates that preoperative risk for 
delirium significantly moderated the effect of postoperative pain and opioid use on the development of 
delirium.  This study illustrates the importance of moderators in influencing risk models of delirium.
 
) – our group is experienced in conducting large-
Experience in conducting randomized control trial (RCT
scale RCT.  We have recruited over 700 patients in a study currently funded by the NIH to validate the 

results of a pilot study showing that gabapentin as an add-on agent in the treatment of postoperative pain 
in older patients undergoing spinal surgery reduced postoperative delirium (29).  Recruitment of this study 
is close to completion and we expect results in 3 months.
 
12.3  References:
1.         Lipowski Z. Delirium (acute confusional states). JAMA. 1987;258:1789-92.
2.         Lipowski Z. Delirium in the elderly patient. New Engl J Med. 1989;320:578-82.
3.         Inouye S. The dilemma of delirium:  clinical and research controversies regarding diagnosis and 
evaluation of delirium in hospitalized elderly medical patients. Am J Med. 1994;97:278-88.
4.         Modena M, Muia N, Sgura F, Molinari R, Castella A, Rossi R. Left atrial size is the major predictor 
of cardiac death and overall clinical outcome in patients with dilated cardiomyopathy:  a long-term follow-
up study. Clin Cardiol. 1997;20:553-60.
5.         Moller J, Cluitmans P, Rasmussen L, Houx P, Rasmussen H, Canet J, et al. Long-term 
postoperative cognitive dysfunction in the elderly:  ISPOCD1 study. Lancet. 1998;351:857-61.
6.         Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K, et al. Postoperative cognitive 
dysfunction in middle-aged patients. Anesthesiology. 2002;96(6):1351-7.
7.         Rasmussen LS, Johnson T, Kuipers HM, Kristensen D, Siersma VD, Vila P, et al. Does anaesthesia 
cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 
438 elderly patients. Acta anaesthesiologica Scandinavica. 2003;47(3):260-6.
8.         Phillips-Bute B, Mathew JP, Blumenthal JA, Grocott HP, Laskowitz DT, Jones RH, et al. Association 
of neurocognitive function and quality of life 1 year after coronary artery bypass graft (CABG) surgery. 
Psychosom Med. 2006;68(3):369-75. Epub 2006/06/02.
9.         Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS. Long-term consequences of 
postoperative cognitive dysfunction. Anesthesiology. 2009;110(3):548-55. Epub 2009/02/20.
10.       Inouye S, Charpentier P. Precipitating factors for delirium in hospitalized elderly 
persons:  predictive model and interrelationship with baseline vulnerability. JAMA. 1996;275:852-7.
11.       Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a 
systematic review. Journal of the American Geriatrics Society. 2006;54(10):1578-89.
12.       Marcantonio E, Goldman L, Mangione C, Ludwig L, Muraca B, Haslauer C, et al. A clinical prediction 
rule for delirium after elective noncardiac surgery. JAMA. 1994;271:134-9.
13.       Leung JM, Sands LP, Paul S, Joseph T, Kinjo S, Tsai T. Does postoperative delirium limit the use of 
patient-controlled analgesia in older surgical patients? Anesthesiology. 2009;111(3):625-31. Epub 2009/08
/13.
14.       Flink BJ, Rivelli SK, Cox EA, White WD, Falcone G, Vail TP, et al. Obstructive sleep apnea and 
incidence of postoperative delirium after elective knee replacement in the nondemented elderly. 
Anesthesiology. 2012;116(4):788-96. Epub 2012/02/18.
15.       Sieber FE, Zakriya KJ, Gottschalk A, Blute MR, Lee HB, Rosenberg PB, et al. Sedation depth during 
spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture 
repair. Mayo Clinic proceedings Mayo Clinic. 2010;85(1):18-26. Epub 2010/01/01.
16.       Radtke FM, Franck M, Lendner J, Kruger S, Wernecke KD, Spies CD. Monitoring depth of 
anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative 
cognitive dysfunction. British journal of anaesthesia. 2013;110 Suppl 1:i98-105. Epub 2013/03/30.
17.       Chan MT, Cheng BC, Lee TM, Gin T. BIS-guided anesthesia decreases postoperative delirium and 
cognitive decline. J Neurosurg Anesthesiol. 2013;25(1):33-42. Epub 2012/10/03.
18.       Farag E, Chelune GJ, Schubert A, Mascha EJ. Is depth of anesthesia, as assessed by the Bispectral 
Index, related to postoperative cognitive dysfunction and recovery? Anesthesia and analgesia. 2006;103
(3):633-40.
19.       An J, Fang Q, Huang C, Qian X, Fan T, Lin Y, et al. Deeper total intravenous anesthesia reduced 
the incidence of early postoperative cognitive dysfunction after microvascular decompression for facial 
spasm. J Neurosurg Anesthesiol. 2011;23(1):12-7. Epub 2011/01/22.
20.       Babiloni C, Carducci F, Lizio R, Vecchio F, Baglieri A, Bernardini S, et al. Resting state cortical 
electroencephalographic rhythms are related to gray matter volume in subjects with mild cognitive 
impairment and Alzheimer's disease. Human brain mapping. 2013;34(6):1427-46. Epub 2012/02/15.
21.       Dijkstra JB, Houx PJ, Jolles J. Cognition after major surgery in the elderly: test performance and 
complaints. British journal of anaesthesia. 1999;82(6):867-74.
22.       Avidan M, Searleman A, Storandt M, Barnett K, Vannucci A, Saager L, et al. Long-term cognitive 
decline in elderly people was not attributable to non-cardiac surgery or major illness. Anesthesiology. 2009;
111:964-70.
23.       Mason SE, Noel-Storr A, Ritchie CW. The impact of general and regional anesthesia on the 
incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review with 
meta-analysis. Journal of Alzheimer's disease : JAD. 2010;22 Suppl 3:67-79. Epub 2010/09/23.
24.       Behrends M, DePalma G, Sands L, Leung J. Association between intraoperative blood transfusions 
and early postoperative delirium in older adults. Journal of the American Geriatrics Society. 2013;61(3):
365-70. Epub 2013/03/19.

25.       Hirsch J, DePalma G, Tsai T, Sands L, Leung J. Intraoperative Blood Pressure Variance, Not 
Hypotension Impacts Early Postoperative Delirium.  Annuall Meeting of the American Society of 
Anesthesiologists; San Francisco, CA 2013.
26.       Leung JM, Sands LP, Lim E, Tsai TL, Kinjo S. Does Preoperative Risk for Delirium Moderate the 
Effects of Postoperative Pain and Opiate Use on Postoperative Delirium? The American journal of geriatric 
psychiatry : official journal of the American Association for Geriatric Psychiatry. 2013;10:946-56.
27.       Leung J, Sands L, Mullen E, Wang Y, Vaurio L. Are preoperative depressive symptoms associated 
with postoperative delirium in geriatric surgical patients? J Gerontology: Medical Sciences. 2005;60A:1563-
8.
28.       Leung JM, Tsai TL, Sands LP. Brief report: preoperative frailty in older surgical patients is 
associated with early postoperative delirium. Anesthesia and analgesia. 2011;112(5):1199-201. Epub 2011
/03/05.
29.       Leung J, Sands L, Rico M, Petersen K, Rowbotham M, Dahl J, et al. Pilot clinical trial of gabapentin 
to decrease postoperative delirium in older surgical patients. Neurology. 2006;67:1-3.
30.       Sessler DI, Sigl JC, Kelley SD, Chamoun NG, Manberg PJ, Saager L, et al. Hospital stay and 
mortality are increased in patients having a "triple low" of low blood pressure, low bispectral index, and 
low minimum alveolar concentration of volatile anesthesia. Anesthesiology. 2012;116(6):1195-203. Epub 
2012/05/02.
31.       Drover D, Ortega HR. Patient state index. Best practice & research Clinical anaesthesiology. 2006;
20(1):121-8. Epub 2006/04/26.
32.       Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild 
cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-
Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & 
dementia : the journal of the Alzheimer's Association. 2011;7(3):270-9. Epub 2011/04/26.
33.       Ward A, Arrighi HM, Michels S, Cedarbaum JM. Mild cognitive impairment: disparity of incidence 
and prevalence estimates. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2012;8(1):
14-21. Epub 2012/01/24.
34.       Taylor KI, Salmon DP, Rice VA, Bondi MW, Hill LR, Ernesto CR, et al. Longitudinal examination of 
American National Adult Reading Test (AMNART) performance in dementia of the Alzheimer type (DAT): 
validation and correction based on degree of cognitive decline. Journal of clinical and experimental 
neuropsychology. 1996;18(6):883-91. Epub 1996/12/01.
35.       Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. Journal of clinical and experimental 
neuropsychology. 1998;20(3):310-9. Epub 1998/12/09.
36.       Morgan DR, Linck J, Scott J, Adams R, Mold J. Assessment of the RBANS Visual and Verbal Indices 
in a sample of neurologically impaired elderly participants. The Clinical neuropsychologist. 2010;24(8):
1365-78. Epub 2010/10/19.
37.       Beglinger LJ, Duff K, Allison J, Theriault D, O'Rourke JJ, Leserman A, et al. Cognitive change in 
patients with Huntington disease on the Repeatable Battery for the Assessment of Neuropsychological 
Status. Journal of clinical and experimental neuropsychology. 2010;32(6):573-8. Epub 2009/11/03.
38.       Wang Y, Sands L, Vaurio L, Mullen A, Leung J. The effects of postoperative pain and its 
management on postoperative cognitive dysfunction. The American journal of geriatric psychiatry : official 
journal of the American Association for Geriatric Psychiatry. 2007;15:50-9.
39.       DeCrane S, Sands L, Lim E, Tsai T, Leung J. Impact of Missing Data on Analysis of Postoperative 
Cognitive Decline (POCD). Applied Nursing Research. 2013;26: 71–5.
40.       Inouye S, van Dyke C, Alessi C, Balkin S, Siegal A, Horwitz R. Clarifying confusion:  the confusion 
assessment method. Ann Intern Med. 1990;113:941-8.
41.       Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The Memorial Delirium Assessment 
Scale. J Pain Symptom Manage. 1997;13(3):128-37.
42.       Sheikh J, Yesavage J. Geriatric Depression Scale (GDS): Recent evidence and development of a 
shorter version. In: Brink T, editor. Clinical Gerontology, A Guide to Assessment and Intervention. New 
York: The Haworth Press; 1986. p. 165-73.
43.       Leung J, Dzankic S. Relative importance of preoperative health status versus intraoperative factors 
in predicting postoperative adverse outcomes in geriatric surgical patients. Journal of the American 
Geriatrics Society. 2001;49:1080-5.
44.       Manku K, Bacchetti P, Leung JM. Prognostic significance of postoperative in-hospital complications 
in elderly patients. I. Long-term survival. Anesthesia and analgesia. 2003;96(2):583-9.
45.       Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality 
Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-213. Epub 
1989/05/01.
46.       Decrane SK, Sands LP, Young KM, Depalma G, Leung JM. Impact of missing data on analysis of 
postoperative cognitive decline (POCD). appl Nurs Res. 2013. Epub 2013/01/08.
47.       Wechsler D. Wechsler Adult Intelligence Scale-Revised Manual. The Pyschological Corporation. New 
York1981.
48.       Borkowski J, Benton A, Spreen O. Word fluency and brain damage. Neuropsychologia. 1967;5:135-
40.
49.       Delis D, Kramer J, Kaplan E, Ober B. California Verbal Learning Test: Adult Version. San Antonio, 
TX: The Psychological Corporation, 1987.
50.       Sands L, Katz I, Doyle S. Detecting subclinical change in cognitive functioning in older adults.  Part 
II: Initial validation of the method. Am J Geriatr Psychiatry. 1994;1(4):275-87.

51.       Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K, et al. Postoperative cognitive 
dysfunction in middle-aged patients. Anesthesiology. 2002;96(6):1351-7.
52.       Sands L, Katz I, Doyle S. Detecting subclinical change in cognitive functioning in older adults.  Part 
II: Initial validation of the method. The American journal of geriatric psychiatry : official journal of the 
American Association for Geriatric Psychiatry. 1993;1(4):275-87.
53.        Wang Y, Sands L, Vaurio L, Mullen A, Leung J. The effects of postoperative pain and its 
management on postoperative cognitive dysfunction. The American journal of geriatric psychiatry : official 
journal of the American Association for Geriatric Psychiatry. 2007;15:50-9.
 
If you have a separate bibliography, attach it to the submission with your other study documents. 
13.0
 Sample Size and Eligibility
13.1  Number of subjects that will be enrolled at UCSF and affiliated institutions:
204
13.2  Total number of subjects that will be enrolled at all sites 
:
(Help Text updated 9/13)
204
13.3  Estimated number of people that you will need to consent and screen here (but not necessarily 
enroll) to get the needed subjects:
300
13.4  Explain how and why the number of subjects was chosen 
:
(Help Text updated 9/13)
Annually, over 1000 patients ≥ 45 years of age undergo major non-cardiac surgery at the University of 
California, San Francisco Medical Center (2013 operating room data).  Therefore, our plan of recruiting 102 
patients per year for 2 years is feasible.  The sample size calculation is based on an incident postoperative 
delirium rate of 40% in the three days after surgery (15, 26).  We anticipate reduction to 22%, power 0.8, 
resulting in 102 patients in each group. This sample size is adequate to detect declines in postoperative 
cognitive functioning across the repeated assessments of cognitive functioning.
 
13.5  * Eligible age range(s):
0-6 years
7-12 years
13-17 years
18+ years
13.6  Inclusion criteria:
≥  45 years of age
English speaking
Not anticipated to be intubated postoperatively
We will be controlling for the effect of surgery statistically by surgery type.
Postoperative stay of 2 days of more to allow for postoperative cognitive testing
 
13.7  Exclusion criteria:

Patients who cannot complete the neurocognitive testing including those who will be expected to remain 
intubated postoperatively.
Patients who are unable to provide informed consent.
Patients who are non-English speaking precluding the administration of neurocognitive tests.
We believe avoiding burst suppression should not be a risk and is not considered light anesthesia per se, 
however we will exclude patients who may not tolerate light anesthesia - history of untreated 
hypertension, unstable cerebrovascular disease including stroke, cardiovascular disease including 
symptomatic heart failure and unstable angina, and patients with a history of intraoperative recall.
 
13.8  There are inclusion or exclusion criteria based on gender, race or ethnicity:
  Yes   
  No
If
, please explain the nature and rationale for the restrictions:
 yes
14.0
 Drugs and Devices
14.1  
Investigational drugs or biologics will be used 
approved drugs or biologics will be studied 
* 
OR 
under this application:
  Yes   
  No
14.2  
edical devices or in vitro diagnostics will be used 
 approved medical devices or 
* Investigational m
OR
in vitro diagnostics will be studied under this application:
 Yes   
 No
14.3  
A Non-Significant Risk (NSR) determination is being requested for an investigational device:
* 
  Yes   
  No
14.4  
  If the sponsor’s protocol does not list the IND/IDE number, you 
Verification of IND/IDE numbers:
must submit documentation from the sponsor or FDA identifying the IND/IDE number for this study. 
Attach this documentation in the Other Study Documents section of the Initial Review Submission 
Packet.
15.0
 Study Device Details
15.1  List the medical devices or in vitro diagnostics to be studied or used and attach any FDA or sponsor 
correspondence relating to the device to the application in the Study Documents section:   (Note: 
Device category descriptions added to the Help link December, 2014)
View 
Details
Device Name
Is the Device FDA 
Approved
Is this a new 
device or a new 
use of an already 
approved device
IDE Number
Sedline Brain Function Monitor 
Yes 
No 
 
Manufacturer/Supplier of Device
Masimo Inc. 
Medicare Category
A
B
Where will the Devices Be Stored
Leung Research Lab: U-368-P 
Will Devices be supplied at no Cost
Yes 

Is this a HUD (HDE)
No 
HDE Number
 
Is the Device FDA Approved
Yes 
Is this a new device or a new use 
of an already approved device
No  
Is an IDE necessary
No  
IDE Number
 
Who holds the IDE
N/A  
IDE Details
The device is being used in accordance with its FDA-approved 
labeling.  
In the opinion of the sponsor, 
select the level of risk associated 
with this device
No Significant Risk  
16.0
 Other Approvals and Registrations
16.1  
 
Do any study activities take place on patient care units:
* 
 Yes   
 No
If 
, attach a letter of support for the study from the involved patient care manager(s).
Yes
16.2  
Does your protocol involve any radiation exposure to patients/subjects? The UCSF Radiation 
* 
 
Safety Committee requires review of your protocol if it includes administration of radiation as part of 
standard of care 
 research exposures:
OR
  Yes   
  No
16.3  
This study may generate genetic data that may be broadly shared (e.g. submitted to NIH for 
* 
 in 
, 
, etc):
Genome-Wide Association Studies (GWAS)
dbGaP TCGA
  Yes   
  No
16.4  
This study involves administration of vaccines produced using recombinant DNA technologies to 
* 
human subjects:
  Yes   
  No
16.5  
This study involves human gene transfer (NOTE: Requires NIH Recombinant DNA Advisory 
* 
Committee (RAC) review prior to CHR approval):
  Yes   
  No
16.6  This study involves other regulated materials and requires approval and/or authorization from the 
following regulatory committees:
Institutional Biological Safety Committee (IBC)
Specify BUA #:
Institutional Animal Care and Use Committee (IACUC)

Specify IACUC #:
Radiation Safety Committee
Specify RUA #:
Radioactive Drug Research Committee (RDRC)
Specify RDRC #:
Controlled Substances
17.0
 Procedures
17.1  
Procedures/Methods 
* 
(Help Text updated 9/13)   For clinical research list all study procedures, test 
and treatments required for this study, including when and how often they will be performed. If 
there are no clinical procedures, describe the Methods:
The incidence and duration of postoperative delirium assessments will be conducted daily for up 
Overview: 
to 7 days after surgery.  For those who stay for more than one week, we will interview them weekly until 
discharge. Cognitive status also will be measured preoperatively, daily for one week, once weekly for those 
staying for more than one week. Postoperatively, patients will be contacted 1 month later and 3 months 
later after surgery for follow-up assessments.
Anesthetic management: the types of anesthetics will not be controlled but will be recorded and analyzed 
as this is a pragmatic trial.  Anesthesiologists will be requested to maintain patients’ arterial blood 
pressure to within 20% of preoperative baseline using vasoactive agents.  Patients will receive mechanical 
ventilation to maintain normocarbia.  Intraoperative warming devices will be used to keep body 
temperature between 36-37 °C.  Oxygen saturation will be maintained at >95% throughout 
surgery.  Muscle relaxants will be used during tracheal intubation and only as clinically indicated at other 
time period during surgery.  Patients will be randomized by a random number generation computer into 
receiving either EEG guided anesthetic depth management vs. standard care.  Anesthesiologists caring for 
patients in the EEG-guided group will keep the PSI >35 to avoid burst suppression.  In our prior pilot 
study, burst suppression occurs in less than 10% of patients when the PSI >35.  Anesthesiologists 
assigned to patients in the standard care group will be blinded to the PSI data.  A Sedline monitor will be 
placed on the patients randomized to receive standard care, but the screen will be covered.  As brain 
monitor is not typically used in standard care of the surgical patients at UCSF, the blinding of the 
monitoring information is consistent with standard care.  In addition to the PSI, we will also record 
indicators of depth of anesthesia including automatic and somatic responses.  Autonomic signs will include 
heart rate and blood pressure changes, diaphoresis, and lacrimation.  Somatic signs will include movement 
in cases when muscle relaxants will not be used.   Explicit recall will be measured.  We will measure 
anesthesiologists’ perceived barrier to adhering to the assigned anesthetic depth by a short self-report at 
the end of each anesthetic. The questions will determine whether the anesthesiologist had difficulty 
attaining the level of anesthetic depth as specified in the protocol and reasons why they could not, 
including hemodynamic instability, patient movement, etc.
In the study, we will request that the anesthesia providers to not continue giving paralytic drugs after 
tracheal intubation unless it is clinically indicated.
In addition, we will monitor and record the use and dosages of all paralytic drugs used during surgery.
 All patients will be continuously monitored before the induction of 
Measurement of anesthetic depth:
anesthesia and during surgery with the SEDline Brain Function Monitor (Masimo, Inc., Irvine CA), which 
provides 4 channels of EEG sampled at 2500 Hz.  EEG signals will be filtered and decimated to 250 samples
/second with an acquisition bandwidth of 0.5 to 70 Hz.  The acquisition montage includes electrodes placed 
according to the International 10-20 System – Fp1, Fp2, F7, and F8, each referenced to FpZ.  EEG data 
will be stored in a proprietary data format and subsequently converted to the EEG industry standard, 
European Data Format (EDF).  In addition, using proprietary software, a continuous display of the 
anesthetic depth, known as the patient state index (PSI) will be displayed and recorded continuously.  The 
PSI is a clinically validated measure of the effect of anesthesia and sedation (31).  Both the raw EEG data 
and the PSI data will be stored on computer for analysis.  We will analyze PSI by examining the total time 
that each patient is kept within the prescribed level of anesthetic depth, and the amount of time outside of 
the assigned range.
 Postoperative cognitive dysfunction will be measured by the digit 
Measurement of Cognitive Status:
symbol substitution test (47) the timed verbal fluency test, (48) and the word list learning task (49) in 
order to assess the cognitive domains of memory and learning (word list), verbal and language skills 

(verbal fluency), attention, concentration, and perception (digit symbol test).  These tests target domains 
that are sensitive to drug effects (50) but have been used and validated in a large number of older surgical 
patients (51).
Alternate forms will be administered at each testing interval, using a Latin-square design. Cognitive 
assessments will be conducted daily for up to 7 days after surgery.  For those who stay for more than one 
week, we will interview them weekly until discharge. We have successfully collected cognitive data from 
more than 600 older surgical patients and have described predictors and outcomes of POCD (38) and 
developed and validated procedures for handling missing data (39).  For each test, we will determine 
whether the patient experienced a significant decline from preoperative baseline using prediction intervals 
(50). A decline from preoperative performance of 4 or more points for the word list, or 7 or more points for 
the verbal fluency and the digit symbol tests is considered significant decline and the subject will be 
classified as having POCD for that day.  If decline in performance is observed for at least one postoperative 
day, we will conclude that POCD occurs for that patient. Prediction intervals consider initial level of 
functioning, learning effects, and correlations between repeated responses unlike other studies of POCD 
that rely on determining incidence based on sample norms and not change in the individual’s level of 
performance.
 For the occurrence of delirium, we will use the Confusion Assessment Method 
Measurement of Delirium:
Rating Scale (CAM) (40) which was developed as a screening instrument based on operationalization of 
DSM-III-R criteria for use by nonpsychiatric clinicians in high-risk settings. The postoperative delirium and 
cognitive assessments will be conducted daily for up to 7 days after surgery.  For those who stay for more 
than one week, we will interview them weekly until discharge by research assistant blinded to the 
randomization.  During the interview, we will check immediate recall of a story and interview a family 
member or physician/nurse to determine if the patient had experienced an acute change in mental status 
prior to the preoperative assessment as defined by the CAM.  This method has a sensitivity of 94-100% 
and a specificity of 90-95% and has a high interobserver reliability (40), and have convergent agreement 
with four other mental status tests.  The research assistant will be trained in the use of the CAM until the 
inter-rater reliability between Dr. Sands and trainee reaches 0.96.  That training will be based on a 
detailed manual developed by Inouye et al. for administration of the CAM (40).  For the severity of 
delirium, we will use the Memorial Delirium Assessment Scale (MDAS) (41) to rate delirium severity.
 We will collect additional variables that have been 
Other variables associated with incident delirium:
shown in prior work to be associated with delirium to ensure that our randomization resulted in groups 
with equivalent predisposition for incident postoperative delirium.  The additional variables will include 
demographic characteristics such as marital status, level of education, living situation, and co-
morbidities.  Pre- and post-operative pain will be measured by the visual analog scale.  Mood will be 
measured preoperatively using the Geriatric Depression Scale (42).  Information on anesthetic agents, 
doses, anesthetic risk, surgery duration and risk, estimated blood loss, etc. will be obtained by reviewing 
the anesthesia record.  Patients’ medical records will be reviewed to obtain the type and daily doses of all 
opioid analgesics used during the intraoperative period and also daily during the postoperative period until 
discharge.  The type and quantity of all other less commonly used analgesics and all medications with 
central nervous system effects will also be measured.  Intraoperative systolic, mean and diastolic blood 
pressure and heart rate will be continuously downloaded onto a computer for subsequent 
analysis.  Increases or decreases from each patient’s preoperative baseline values and absolute values will 
be measured using methods previously published by us (25).  The use and quantity of vasoactive agents 
used during surgery will also be measured.  The occurrence of other postoperative adverse outcomes will 
be measured using pre-defined criteria developed by our previous studies (43, 44).  Since sleep 
disturbance has been suggested to increase the risk of delirium in hospitalized elders, we will measure self 
reported sleep abnormalities using the Pittsburgh Sleep Quality Index (45), a self-administered survey, 
preoperatively and also daily for the first week after surgery and at discharge.
Postoperative follow-up:
After hospital discharge, patient will be contacted by phone at one month and three months 
postoperatively for evaluation of their functional status, pain and sleep problems. The cognitive status will 
be evaluated by Telephone Interview of Cognitive Status, and the symptoms of depression by the Geriatric 
Depression Scale.
 
If you have a procedure table, attach it to the submission with your other study documents.
17.2  Interviews, questionnaires, and/or surveys will be administered or focus groups will be conducted:
 Yes   
 No
List any standard instruments used for this study:  
Telephone Interview of Cognitive Status (telephone version of Mini Mental status examination)
Geriatric depression scale
Confusion Assessment Method

Neurocognitive tests (Digit Symbol, Word list, Verbal fluency, Digit Span)
Pittsburgh Sleep Quality Index: a self-administered survey, which measures sleep abnormalities.
Brice Scale: Assesses awareness during anesthesia with subsequent explicit recall
Visual Analog Scale
 
 
Attach any non-standard instruments at the end of the application.
17.3  Conduct of study procedures or tests off-site by non-UCSF personnel:
  Yes   
  No
If yes, explain:
17.4  Sharing of experimental research test results with subjects or their care providers:
  Yes   
  No
If yes, explain:
17.5  
Specimen collection for future research and/or specimen repository/bank administration:
* 
 Yes   
 No
17.6  Time commitment (per visit and in total):
Cognitive status will be measured preoperatively, daily for one week, and at 6 weeks after surgery.  Approx
imately 15 minutes on average will be required to complete the neurocognitive testing for each day of testing. 
Testing will take slightly longer if a patient is confused after surgery.  Participation in the study will take a total of 
about 2.5 hours.  Anesthetic depth monitoring will not require any additional time commitment.
17.7  Locations:
Prepare clinic or inpatient ward (preoperative neurocognitive testing)
UCSF Moffitt-Long operating rooms
Orthopaedic Institute Clinic operating rooms
 
17.8  Describe the resources in place to conduct this study in a way that assures protection of the rights 
and welfare of participants:
If the studied patients are injured as a result of being in the study, treatment will be available. The costs of such 
treatment may be covered by the University of California, San Francisco.  
 
18.0
 Specimen Collection for Future Research and/or 
Specimen Repository/Bank Administration
18.1  Specimens are (check all that apply):
Surplus clinical specimens from a diagnostic or therapeutic procedure

Specimens collected for research purposes only
Other
If Other, explain:
Patients who had preoperative laboratory tests relating to their planned surgery would provide consent to 
have this "to be discarded blood" banked after routine clinical laboraotry testing performed. This left over 
blood is normally discarded after clinical testing but we propose to preserve the blood for tissue banking.
18.2  Types of specimens: 
Blood
Tissue (describe below):
Existing/archival materials (name source below): --
Other (describe below):
Describe and/or name source:
18.3  Consent will be obtained via:
Separate specimen banking consent form
Specimen banking section within a main research study consent form
Surgical consent form with tissue donation brochure
18.4  Specimens will ultimately be stored (check all that apply):
UCSF
UCSF repository/bank being established under this protocol
Existing UCSF specimen repository/bank with CHR approval
Provide the name of the bank and CHR approval number (if not being banked at UCSF under this 
protocol):
Outside Entity
Cooperative group bank
NIH
Other university
Industry sponsor
Other
Specify to what institution, cooperative group or company specimens will be transferred:
18.5  Direct identifiers will be sent with specimens or shared with other researchers and/or outside 
entities:
Yes 
No 
N/A - Specimens will not be shared with others 
If 
, which identifiers will be sent with specimens:
Yes
Name

Date of birth
Social Security number
Medical record number
Address
Phone number
Email address
Other dates (surgery date, clinic visit dates, etc.)
If 
, provide a justification for sending direct identifiers with the specimens:
Yes
19.0
 Establishing a Specimen Repository/Bank at UCSF
19.1  The repository/bank is physically located at (list the address and room number for all locations):
San Francisco General Hospital & Trauma Center
1001 Potrero Ave., Room 2M27
San Francisco, CA 94110
19.2  Methods for maintaining confidentiality:
Samples are completely de-identified before being added to the bank/repository. There is no way to 
link the specimens back to the subjects.
Samples are coded and researchers are able to link the specimens to specific subjects. However, 
future recipients will not receive direct identifiers with the specimens.
Samples are stored with direct identifiers in the repository. However, future recipients will not receive 
direct identifiers with the specimens.
Samples are coded and/or kept with direct identifiers in the repository. The bank/repository may 
release identifiers with specimens to researchers under special circumstances with prior IRB approval.
Explain under what circumstances identifiers may be released:
19.3  If the repository/bank maintains the identifiers, list the identifiers that will be maintained with the 
specimens:
Name
Date of birth
Social Security number
Medical record number
Address
Phone number
Email address
Other dates (dates of surgery, visit dates)
19.4  Clinical follow-up data will be linked to specimens:
 Yes   
 No
If 
, provide duration of follow-up or indefinitely:
Yes
Till the subject has deceased, for survival analyses.
19.5  There is a formal specimen utilization review process:
  Yes   
  No

If 
, describe the process:
Yes
19.6  Specimens banked at UCSF may be made available to (check all that apply):
UCSF researchers
Non-UCSF researchers
Industry
20.0
 Alternatives
20.1  Study drug or treatment is available off-study:
Yes 
No  
Not applicable 
20.2  
Is there a standard of care (SOC) or usual care that would be offered to prospective subjects at 
* 
UCSF (or the study site) if they did not participate:
 Yes   
 No
If yes, describe the SOC or usual care that patients would receive if they choose not to participate:
If the patient choose not to participate in the study, usual standard clinical care will be performed with 
patient's consent. Currently, anesthetic depth monitors such as BIS or SEDline are not being used 
routinely during surgery. Anesthetic depth is being estimated by patients' hemodynamics, end-tidal 
anesthetic concentrations, and known pharmacology of other intravenous drugs.
 
20.3  Describe other alternatives to study participation that are available to prospective subjects:
If the patient chooses not to participate in the study, usual clinical care will be performed with 
Currently, anesthetic depth monitors such as BIS or SEDline are not being used 
patient's consent. 
routinely during surgery. Anesthetic depth is being estimated by patients' hemodynamics, end-tidal 
anesthetic concentrations, and known pharmacology of other intravenous drugs.
 
21.0
 Risks and Benefits
21.1  
Risks and discomforts:
* 
General anesthetics by themselves are generally safe in healthy individuals.  Depending on the co-existent 
diseases of the patients, there may be individual anesthesia related risks that are inherent to patients 
undergoing major non-cardiac surgery such as blood loss necessitating intraoperative blood transfusion, 
and position related injuries, etc.  Specific study-related risks pertaining to the randomization of anesthetic 
depths may include sympathetic activation (increases in blood pressure and/heart rate) which may 
necessitate treatment with vasoactive medications such as beta adrenergic blocking agents, and/or anti-
hypertensive agents; patient recall of intraoperative events; or patient movement during surgery – these 
events may be more likely to occur in patients randomized to receiving EEG-guided anesthesia 
management.  For patients randomized to receive standard care, there is no known risk other as brain 
monitor is not routinely used at UCSF during surgery. We will discuss these risks in more details in the 
data safety monitoring process below.
 

21.2  Steps taken to minimize risks to subjects:
To minimize potential risks to subjects, we will carefully monitor the recruitment, enrollment and retention 
of study subjects.  We will monitor the occurrences of potential study related outcomes include compliance 
to the randomization, and safety measurements such as sympathetic activation, hypotension, 
intraoperative recall, or intraoperative patient movements. The first safety review will take place after the 
first month or after the first 10% of the subjects are enrolled, whichever will come first.  All study end-
points will be closely defined to facilitate ease of monitoring. We will exclude subjects with a history of 
untreated hypertension, unstable cerebrovascular disease including stroke, and cardiovascular disease 
including symptomatic heart failure and unstable angina, and patients with a history of intraoperative 
recall. In addition, we will form a data safety monitoring board to consist of individuals not connected to 
the study.  When the study receives funding, the DSMB membership will consist of individuals not related 
to UCSF.
 
 
21.3  Benefits to subjects:
 
  Yes   
  No
If yes, describe:
21.4  Benefits to society:
 From a scientific innovation standpoint, our study will provide a mechanistic insight into the possible 
relationship between anesthetic depth and postoperative cognitive outcomes, in particularly, whether 
avoiding burst suppression is beneficial has not been previously evaluated.
     Another clinical relevance of our approach is that we have substantial prior experience in modeling of 
the impact of baseline vulnerabilities on perioperative and long-term outcomes.  This experience will help 
us to evaluate whether randomization resulted in groups with equivalent baseline characteristics known to 
affect postoperative cognitive outcomes.  Information learned from our studies will help to inform patients, 
families, and physicians alike of the short- and long-term impact of surgery given the baseline 
vulnerabilities.
     Because postoperative delirium and cognitive decline are prevalent in the surgical patients and are 
associated long-term poor outcomes, our study results are critical to understanding how preoperative 
cognitive status moderates anesthetic depth on postoperative cognitive outcomes.  This knowledge is 
critical for patient informed consent, care management, and development of future interventions to 
improve the perioperative and post-discharge care of these older patients.
As a result, we believe that the risks involved (loss of privacy as discussed previously, and minor 
inconvenience from delirium measurements, cognitive testing, and randomization to EEG-guided 
anesthesia management are reasonable in relation to the importance of the knowledge that is expected to 
be gained as a result of the study.
 
21.5  Explain why the risks to subjects are reasonable: 
Recently, some in the anesthesia field advocate that older patients should be routinely monitored by 
anesthetic depth monitor to avoid deep levels of anesthesia and its potentially adverse effects on 
postoperative cognition.  The implication that anesthetic is potentially toxic raises a public health concern 
that has not been thoroughly validated.  Our proposed study will provide essential data to guide a larger 
randomized clinical trial to determine if avoiding burst suppression (hence much deeper level of 
anesthesia) will lead to better cognitive outcomes for the older patients after major surgery.
 
22.0
 Data and Safety Monitoring Plan
22.1  Describe the plan for monitoring data and safety 
:
(Help Text updated 9/13)
Prior to the study, a safety and data monitoring board (DSMB) will be formed to consist of two physicians 
and a statistician not involved in the study.
The DSMB will focus on the following:

            a.         Performance – subject recruitment, retention, and follow-up, flow of data forms, protocol 
adherence and quality of data.
            b.         Safety – the magnitude and frequency of adverse events will be measured.  See safety 
review described below.
            c.         Intervention – we will monitor and assess for intervention effects, this will include the 
intraoperative hemodynamics, dose of intraoperative anesthetics and medications, intraoperative recall, 
anesthesiologists ability to follow the prescribed anesthetic protocols, and other pre-defined adverse 
events.
 
After the study receives funding from the NIH, an extramural DSMB will be formed, and the membership 
will be approved by the NIH.
 
22.2  This study requires a Data and Safety Monitoring Board:
Yes 
No or not sure 
If 
, press 
 to move to the next section of the application.
yes
SAVE and CONTINUE
22.3  If 
, provide rationale:
No
Social/Behavioral research 
Phase I trial 
Treatment IND/Compassionate Use Trial 
Other (explain below) 
If 
 explain:
Other,
23.0
 Data and Safety Monitoring Board
23.1  Provide details from the Data and Safety Monitoring Board's charter, including meeting frequency, 
and affiliations and qualifications of members:
We will form a Data and Safety Monitoring Board (DSMB) to monitor participant safety, data quality, and 
to evaluate the progress of the study.  Once the grant receives funding, we will select up to 5 members to 
sit on the DSMB.  The membership will need to be approved by the NIH funding institute program 
director.  All members of the DSMB will not have a research relationship with the principal investigator or 
co-investigators, and will be all external to the investigators’ institutions.  The chair of the DSMB will also 
serve as a Safety Officer.  The membership will consist of a biostatistician and physician-scientists who will 
be knowledgeable about the question being studied, but not involved in the actual conduct of the study.
23.2  All of the members of the Data and Safety Monitoring  Board are independent of the sponsor:
 Yes   
 No
24.0
 Confidentiality and Privacy
24.1  Plans for maintaining privacy in the research setting:
T e subject’
h
s name will not be used in any published report about this study. All data on each study 
subject will be linked only by the subject’s study number. The original data form containing the subject’s 
personal identifier (such as name, birth date, medical record number) relative to the study number will be 
kept in a locked filing cabinet, inside a double locked room with a keyed entry, and an electronic key entry 
identifying all personnel who accessed the room.

It is possible that the study may identify someone with a high number of symptoms of depression. If a 
patient scores higher than a 6 on the Geriatric Depression Scale, they will be asked if they wish for the 
study to pass along their score to their primary care doctor. If a patient gives permission, the patient's 
name and score will be shared verbally over the phone to the doctor. If a patient refuses permission to 
share this information, then no information will be shared for any reason.
 
24.2  Possible consequences to subjects resulting from a loss of privacy:
Participation in research may involve a loss of privacy, but information about the patient will be handled as 
confidentially as possible. Patient’s name will not be used in any published report about this study.
The patient's personal identifier of name and score on the Geriatric Depression Scale will only be shared to the 
patient's primary physician and only if the patient gives permission.
 
24.3  Study data are:
Derived from the Integrated Data Repository (IDR) or The Health Record Data Service (THREDS) at 
SFGH
Derived from a medical record (e.g. APeX, OnCore, etc. Identify source below)
Added to the hospital or clinical medical record
Created or collected as part of health care
Used to make health care decisions
Obtained from the subject, including interviews, questionnaires
Obtained from a foreign country or countries only
Obtained from records open to the public
Obtained from existing research records
None of the above
If 
, identify source:
derived from a medical record
APeX
24.4  Identifiers may be included in research records:
 Yes   
 No
If 
, check all the identifiers that may be included:
yes
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs

IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
* Required for studies conducted at the VAMC
24.5  Identifiable information might be disclosed as part of study activities:
 Yes   
 No
If 
, indicate to whom identifiable information may be disclosed:
yes
The subject's medical record
The study sponsor
Collaborators
The US Food & Drug Administration (FDA)
Others (specify below)
A Foreign Country or Countries (specify below)
If 
, specify:
Others
CHR and UCSF
24.6  Indicate how data are kept secure and protected from improper use and disclosure (check all that 
apply):   NOTE: Whenever possible, do not store subject identifiers on laptops, PDAs, or other 
portable devices. If you collect subject identifiers on portable devices, you MUST encrypt the devices.
Data are stored securely in My Research
Data are coded; data key is destroyed at end of study
Data are coded; data key is kept separately and securely
Data are kept in a locked file cabinet
Data are kept in a locked office or suite
Electronic data are protected with a password
Data are stored on a secure network
Data are collected/stored using REDCap or REDCap Survey
Data are securely stored in OnCore
24.7  Additional measures to assure confidentiality and protect identifiers from improper use and 
disclosure, if any:
The subject’s name will not be used in any published report about this study. All data on each study subject will be linked 
only by the subject’s study number. The original data form containing the subject’s personal identifier (such as name, birth 
date, medical record number) relative to the study number will be kept in a locked filing cabinet, inside a double locked 
room with a keyed entry, and an electronic key entry identifying all personnel who accessed the room.
 
24.8  This study may collect information that State or Federal law requires to be reported to other officials 
or ethically requires action:
  Yes   
  No
Explain:

This study will not elicit information on suicidal ideation which thus will not require reporting to officials or 
ethically requiring action.
24.9  This study will be issued a Certificate of Confidentiality:
  Yes   
  No
25.0
 Subjects
25.1  Check all types of subjects that may be enrolled:
Inpatients
Outpatients
Healthy volunteers
Staff of UCSF or affiliated institutions
25.2  Additional vulnerable populations:
Children
Subjects unable to consent for themselves
Subjects unable to consent for themselves (emergency setting)
Subjects with diminished capacity to consent
Subjects unable to read, speak or understand English
Pregnant women
Fetuses
Neonates
Prisoners
Economically or educationally disadvantaged persons
Investigators’ staff
Students
Explain why it is appropriate to include the types of subjects checked above in this particular study:
Describe the additional safeguards that have been included in the study to protect the rights and welfare 
of these subjects and minimize coercion or undue influence:
26.0
 Recruitment
26.1  
 Methods (check all that apply):
*
Study investigators (and/or affiliated nurses or staff) recruit their own patients directly in person or by 
phone.
Study investigators recruit their own patients by letter. Attach the letter for review.
Study investigators send a “Dear Doctor” letter to colleagues asking for referrals of eligible patients. If 
interested, the patient will contact the PI or the PI may directly recruit the patients (with documented 
permission from the patient). Investigators may give the referring physicians a study information 
sheet for the patients.
Study investigators provide their colleagues with a “Dear Patient” letter describing the study. This 
letter can be signed by the treating physicians and would inform the patients how to contact the study 
investigators. The study investigators may not have access to patient names and addresses for mailing
Advertisements, notices, and/or media used to recruit subjects. Interested subjects initiate contact 
with study investigators. Attach ads, notices, or media text for review. In section below, please explain 
where ads will be posted.

Study investigators identify prospective subjects through chart review. (Study investigators request a 
Waiver of Authorization for recruitment purposes.)
Large-scale epidemiological studies and/or population-based studies: Prospective subjects are 
identified through a registry or medical records and contacted by someone other than their personal 
physician. (Study investigators request a Waiver of Authorization for recruitment purposes.)
Direct contact of potential subjects who have previously given consent to be contacted for participation 
in research. Clinic or program develops a CHR-approved recruitment protocol that asks patients if they 
agree to be contacted for research (a recruitment database) or consent for future contact was 
documented using the consent form for another CHR-approved study.
Study investigators list the study on the School of Medicine list of UCSF Clinical Trials website or a 
similarly managed site. Interested subjects initiate contact with investigators.
Study investigators recruit potential subjects who are unknown to them through methods such as 
snowball sampling, direct approach, use of social networks, and random digit dialing.
Other
If 
, explain:
Other
26.2  
How, when, and by whom eligibility will be determined:
* 
Eligibility will be determined by chart review (age, type of surgery) by either the principal investigator or 
the research associates. This will take place typically from one to seven days before the planned surgical 
procedure.
Inclusion criteria will include that the patient be ≥ 45 years of age, undergoing major non-cardiac surgery 
for whom general anesthesia can be administered, English speaking, and not anticipated to be intubated 
postoperatively.
 
Exclusion criteria will apply when the patient cannot complete the neurocognitive testing including those 
who will be expected to remain intubated postoperatively, are unable to provide informed consent, are non-
English speaking precluding the administration of neurocognitive tests, and may not tolerate light 
anesthesia - history of untreated hypertension, unstable cerebrovascular disease including stroke, 
cardiovascular disease including symptomatic heart failure and unstable angina, and patients with a history 
of intraoperative recall. An additional criterion includes patients with surgical site on the same areas where 
the SEDline forehead sensors will be placed.
 
26.3  
How, when, where and by whom potential subjects will be approached:
* 
As stated above, after a review of their medical record to determine the eligibility criteria, 
potential subjects will be approached by either the principal investigator or one of the trained 
research assistants in either by phone or the Prepare Clinic (preoperative clinic). This will take 
place typically from one to seven days before the planned surgical procedure. The study subjects 
are given as much as time as they wish before signing the informed consent in the preoperative 
period.
The research assistant will follow the phone script. If the patient is interested in participating, he 
or she will be required to sign the consent form in person before the surgery and before he or she 
is officially enrolled in the study. The patient will be sent by mail or email a copy of the 
information sheet.
 
26.4  * Protected health information (PHI) will be accessed prior to obtaining consent:
 Yes   
 No
27.0
 

Waiver of Consent/Authorization for Recruitment 
Purposes
This section is required when study investigators (and/or affiliated 
nurses or staff) recruit their own patients directly.
27.1  
Study personnel need to access protected health information (PHI) during the recruitment process 
* 
and it is not practicable to obtain informed consent until potential subjects have been identified:
Yes 
If 
, a waiver of consent/authorization is NOT needed.
no
27.2  
 A waiver for screening of health records to identify potential subjects poses no more than minimal 
* 
risk to privacy for participants:
Yes 
If 
, a waiver of authorization can NOT be granted.
no
27.3  
Screening health records prior to obtaining consent will not adversely affect subjects' rights and 
* 
welfare:
Yes 
If 
, a waiver of authorization can NOT be granted.
no
27.4  
Check all the identifiers that will be collected prior to obtaining informed consent:
* 
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
None
Note: HIPAA rules require that you collect the minimum necessary.
27.5  
 Describe any health information that will be collected prior to obtaining informed consent:
*

Age, type of surgery, primary language, name, date of surgery, eligibility criteria
 
Note: HIPAA requires that you collect the minimum necessary.
27.6  
Describe your plan to destroy the identifiers at the earliest opportunity consistent with the 
* 
research 
 provide a health or research justification for retaining the identifiers, or indicate and 
or
explain that retention is required by law:
Patient information will be discarded securely.
 
28.0
 Informed Consent
28.1  * Methods (check all that apply):
Signed consent will be obtained from subjects and/or parents (if subjects are minors)
Verbal consent will be obtained from subjects using an information sheet or script
Electronic consent will be obtained from subjects via the web or email
Implied consent will be obtained via mail, the web or email
Signed consent will be obtained from surrogates
Emergency waiver of consent is being requested for subjects unable to provide consent
Informed consent will not be obtained
28.2  
Process for obtaining informed consent:
* 
As stated above, after a review of their medical record to determine the eligibility criteria, potential subjects will 
be approached by either the principal investigator or one of the trained research assistants in either by phone
/mail, the Prepare Clinic (preoperative clinic) or on the ward if they have been pre-admitted for the planned 
surgical procedure. This will take place typically from one to seven days before the planned surgical procedure. 
The study subjects are given as much as time as they wish before signing the informed consent in the 
preoperative period. Due to changing practice in preoperative evaluation, more than 60% of patients do not 
come to the hospital for in person evaluation, but by phone only. Therefore, if the patient’s case is scheduled as 
the first case in the morning, in order not to delay the start of surgery, and to still be able to obtain baseline 
cognitive data, it is more convenient to perform some of the tests on the phone prior to a written consent. For 
any subjects who have provided verbal consent over the phone, a written informed consent will always be 
obtained on the day of surgery when the subjects arrive to the hospital, prior to completing the entire 
preoperative evaluation by the investigators. The preoperative evaluation involves memory tasks, questions 
 
about mental and physical health, and health history. This is done in person or over the phone. If the patient is 
contacted by phone, it will be done by the principal investigator or one of the trained research assistants. For 
any subjects who have provided verbal consent over the phone, a written informed consent, will always be 
obtained on the day of surgery when the subjects arrive to the hospital, prior to completing the entire 
preoperative  evaluation by the investigators.
The study subjects are given as much as time as they wish before agreeing verbally to participate. If the patient 
is interested in participating, the researcher will document the patient's verbal consent and the patient will be 
required to sign the consent form in person before the surgery. A copy of the infomation sheet will be made 
available to individuals providing verbal consent. Depending on the patient's preference, the consent form will 
either be air mailed or electronically mailed to the patient. The preoperative evaluation will be done over the 
phone or in person, before or after the patient's visit to the preoperative clinic, depending on the patient's 
availability. Thus, the preoperative evaluation (memory tasks, questions about mental and physical health, and 
health history) will be done occasionally before the investigator meets with the patient in person and before 
written consent is ultimately obtained. A written cognitive test that takes 2 minutes will be done always in person 
after written consent is obtained.
 

28.3  
How investigators will make sure subjects understand the information provided to them:
* 
The Principal Investigator has been conducting patient related research for over 20 years at UCSF. At the time 
of consenting, we always ask the potential study subjects if they understand the research study and if they have 
any questions before signing the informed consent. Also, a consent form is given to them and all the items 
reviewed systematically with each potential subject.
29.0
 Waiver of Signed Consent (Verbal/Electronic Consent)
29.1  
Select the regulatory category under which the CHR may waive the requirement to obtain 
* 
signed 
consent:
46.117(c) (1) The only record linking the subject and the research would be the consent document and 
the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will 
be asked whether the subject wants documentation linking the subject with the research, and the 
subject's wishes will govern 
46.117(c) (2) The research presents no more than minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside of the research context  
30.0
 Financial Considerations
30.1  Subjects payment or compensation method (check all that apply):
Payments will be (check all that apply):
Subjects will not be paid
Cash
Check
Debit card
Gift card
Reimbursement for parking and other expenses
Other:
Specify 
:
Other
30.2  Describe the schedule and amounts of payments, including the total subjects can receive for 
completing the study. If deviating from recommendations in Subject Payment Guidelines, include 
specific justification below. 
 
 
30.3  Costs to Subjects:  Will subjects or their insurance be charged for any study procedures?
 Yes   
 No
If 
 describe those costs below, and compare subjects’ costs to the costs associated with alternative 
yes,
care off-study. Finally, explain why it is appropriate to charge those costs to the subjects.
Subjects or their insurance will only be charged for standard care for the cost of anesthesia. This is done 
as part of clinical routine practice. 
Subjects wil not be billed for monitoring from the SEDline device.
31.0
 

CTSI Screening Questions
31.1  
This study will be carried out at one of the UCSF Clinical Research Services (CRS) centers or will 
* 
utilize CRS services. CRS centers are at the following sites:
SFGH Clinical Research Center
Moffitt Adult Clinical Research Center
Moffitt Hospital Pediatrics & NCRC
Mount Zion Hospital Clinical Research Center
Tenderloin Center
CHORI Children's Hospital Pediatrics & Adult Clinical Research Center
Kaiser Oakland Research Unit
SF VA Medical Center Clinical Research Unit
  Please note: Effective 3/1/14, the CRS form will no longer be completed and submitted in iRIS. The 
CRS budget request form can be found at: https://accelerate.ucsf.edu/files/crs
 
/BudgetRequest2015.docx. Follow the instructions on the form to submit.  Even if you click 'Yes' to 
this question, the form will no longer proceed to the Clinical Research Services (CRS) Application 
Form section.
  Yes   
  No
31.2  This project involves community-based research:
  Yes   
  No
31.3  This project involves practice-based research:
  Yes   
  No
32.0
 End of Study Application
32.1  End of Study Application Form   To continue working on the Study 
: Click on the section you need to edit in the left-hand menu. Remember to save 
Application
  
through the entire Study Application after making changes.  If you are done working on the 
: Click Save and Continue. If this is a new study, you will automatically 
Study Application
enter the Initial Review Submission Packet form, where you can attach consent forms or 
other study documents. Review the 
 for a list of required 
Initial Review Submission Checklist
 
attachments.   Answer all questions and attach all required documents to speed up your 
 
approval.  

 
 
 
 
 
 
 
  
Human Research Protection Program 
Institutional Review Board (IRB) 
  
Expedited Review Approval 
  
  
Principal Investigator 
Dr. Jacqueline M Leung, MD, MPH 
 
 
 
Type of Submission:  
Continuing Review Submission Form 
Study Title: 
 
The Effect of Anesthetic Depth on Postoperative Cognitive Outcomes, II 
 
 
 
IRB #: 
 
14-14273 
Reference #: 
 
227548 
Committee of Record: 
Laurel Heights Panel 
Study Risk Assignment: Greater than minimal  
  
Approval Date: 
07/25/2018 
Expiration Date: 07/24/2019 
 
  
Regulatory Determinations Pertaining to this Approval: 
   
This submission was eligible for expedited review as:  
Category 8(c): Renewal of inactive research protocols or protocols that are essentially complete: where 
the remaining research activities are limited to data analysis 
  
IRB Comments:  
  
All changes to a study must receive UCSF IRB approval before they are implemented. Follow the 
modification request instructions. The only exception to the requirement for prior UCSF IRB review and 
approval is when the changes are necessary to eliminate apparent immediate hazards to the subject (45 
CFR 46.103.b.4, 21 CFR 56.108.a). In such cases, report the actions taken by following these 
instructions.   
  
Expiration Notice: The iRIS system will generate an email notification eight weeks prior to the expiration 
of this study’s approval.  However, it is your responsibility to ensure that an application for continuing 
review approval has been submitted by the required time. In addition, you are required to submit a study 
closeout report at the completion of the project. 
  
For a list of all currently approved documents, follow these steps: Go to My Studies and open the study – 
Click on Informed Consent to obtain a list of approved consent documents and Other Study Documents 
for a list of other approved documents.  
  
San Francisco Veterans Affairs Medical Center (SFVAMC): If the SFVAMC is engaged in this 
research, you must secure approval of the VA Research & Development Committee in addition to UCSF 
IRB approval and follow all applicable VA and other federal requirements. The UCSF IRB website has 
more information.