Preoperative Cognitive Screening in Older Spinal Surgical Patients: Feasibility and Utility for Predicting Morbidity
Conditions: Cognitive Impairment, Frail Elderly Syndrome
Sponsor: Brigham and Women's Hospital

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Preoperative Cognitive Screening in Older Spinal Surgical Patients 
NCT02922634 
1/28/2021 
Detailed Protocol with Statistical Analysis Plan  
 
 

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Protocol Title: Preoperative Cognitive Screening in Older Thoracic 
and Spinal Surgical Patients: Feasibility and Utility for Predicting 
Morbidity  
 
Background and Significance:   
Approximately 1 of every 3 surgical procedures nationally is 
performed on a patient ≥ 65 years of age yet this demographic 
represents only 13% of the population.1-3 At our institution, a tertiary 
care center, 40% of elective, non-cardiac surgery is performed on 
seniors (see Feasibility Data). This proportion will grow, as seniors 
(defined here and throughout as persons ≥ 65 years) are a fast-
growing segment of the population. Making matters worse, geriatric 
surgical patients often do poorly.2,4-7 Thirty-day mortality for 
community dwelling Medicare enrollees is a remarkable 4.5% for 
appendectomy and 18% for colectomy and double this for nursing 
home residents, and even survivors frequently experience sustained 
functional decline.1,2,4 This places enormous emotional and economic 
burdens on geriatric patients, their families, and the healthcare 
system. The challenge therefore is to identify risk factors for poor 
outcomes preoperatively so that the vital organ function can be 
improved or accommodated in the planning and execution of surgical, 
anesthetic, and postoperative care. Preoperative assessment of vital 
organs—heart, lungs, kidney, liver, blood—has been a staple of 
preparation for surgery for decades, and established algorithms 
address how to evaluate and manage a wide range of conditions 
perioperatively. Oddly, the brain is not among the vital organs that get 
formally evaluated preoperatively.8 For geriatric surgical patients, this 
is a major and likely costly omission because brain dysfunction is 
common in seniors. Five-10% of Americans over age 65 and 25-40% 
of those over 85 have dementia; including MCI (mild cognitive 
impairment), the prevalence of cognitive impairment is 35-50% in 
those ≥ 65 (depending on the age structure of the population and the 
definition and assessment methods used) and higher still in those ≥ 
85.9-11 Therefore, it is reasonable to assume that many seniors 
scheduled for elective surgery have cognitive impairment that goes 
unrecognized. Our preliminary data support that hypothesis. We 
preoperatively screened 289 geriatric elective surgical patients with 
the MiniCog, a brief and well-validated test of visuospatial 
representation, recall, and executive function,12-17 and found, using 
standard cutoffs, that 24% overall and 33% of those ≥ 75 years of age 
scored in a range that suggests functionally meaningful impairment. 
Yet, the intake nurse classified all but one as being cognitively intact, 
including 3 of 4 who had a MiniCog of 0. These results are consistent 
with published data from smaller studies that used similar tools to 

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screen patients ≥ 65 years presenting to an emergency department or 
having surgery with planned admission to the ICU which, depending 
upon the type of cognitive testing and age, show 20% to 63% are 
cognitively impaired.18-21 Thus, there is evidently a problem that goes 
undetected without screening. 
But does it matter? We contend the answer is ‘yes’8 and 
conceptualize cognitive impairment as a form of brain failure that, like 
heart failure, arises from multiple causes but leads independently to 
poor outcomes. Evidence supports this reasoning. First, cognitive 
dysfunction is a risk factor for adverse life events.22 At a minimum, 
therefore, cognitive screening may help identify those least likely to 
benefit from the surgery. Second, routine clinical interactions, whether 
in primary care or hospital settings, are insensitive for detecting 
cognitive impairment or even frank dementia,13,17,23 an observation we 
confirmed in our pilot study (Preliminary Data). Failure to recognize 
the problem could lead to suboptimal outcomes in a surgical setting if 
patients cannot recall what is expected of them postoperatively in 
terms of activity restrictions, wound care, medication regimens, and 
rehabilitation. Third, many seniors experience subtle and long-lasting 
executive dysfunction postoperatively that is independent of the 
specific anesthetic or surgical procedure, suggesting the patient’s 
preoperative cognitive function is a predisposing factor.24-26 Fourth, 
some evidence indicates poor cognitive status increases complication 
risk, undermines the chance of a good outcome, and adds to the cost 
of care. In hospital delirium is a prime example, as it occurs in 15-80% 
of older surgical patients and contributes to poor outcomes.27-30 
Although pre-existing cognitive impairment is an established risk factor 
for delirium, we seldom know a patient’s cognitive status 
preoperatively because it is not currently assessed. Pre-existing 
cognitive impairment may also be a risk factor for serious non-
cognitive morbidity31,32 or mortality in geriatric patients having major 
elective operations19-21 but data on non-cognitive outcomes are limited 
and no such association has been tested in a naturalistic, real-world 
setting (i.e. screening by regular preoperative evaluation center 
staff) such as we propose. Nonetheless, it is noteworthy that brief 
screening tests like the MiniCog were sufficient to detect such 
relationships and that guidelines issued jointly by the American College 
of Surgeons (ACS) and the American Geriatrics Society (AGS) strongly 
recommend routine preoperative cognitive assessment and specifically 
mention the MiniCog, detailed history, and informant questionnaire3—
precisely the tools we propose to use. Still, perhaps because the data 
justifying the recommendation are sparse, it has not been widely 
adopted. 

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With national geriatric surgery volume large and growing and 
morbidity high, better understanding of preoperative cognition as a 
predictor / mediator of outcome has the potential to yield huge clinical 
and economic dividends. Assuming identification of a problem is the 
first step in solving it and that cognitive impairment is a form of brain 
failure, the lack of routine preoperative cognitive screening is 
presumably a major barrier to improving geriatric surgical care. Having 
demonstrated already in 289 patients that MiniCog testing is feasible 
in a preoperative evaluation center and that even non-medical 
personnel can administer and score it reliably (Preliminary Data), we 
are optimistic such screening can be implemented broadly. Unclear, 
however, is whether it is worth doing in terms of providing information 
about cognitive function that is unavailable from standard sources 
(patient/informant inquiry, focused chart review) and whether, like 
dysfunction of other vital organs, preoperative brain dysfunction is 
relevant to the surgical outcome of seniors.  
Because of our success in screening older surgical patient 
undergoing elective surgical procedures we are now investigating 
whether the baseline peripheral immune status as measured by 
inflammatory cytokines in the plasma and white blood cell response to 
an ex-vivo immune challenge is predicted by the patient’s baseline 
cognitive screening score. This will allow us to determine whether an 
exaggerated immune response to the surgery is predictive of adverse 
outcomes in aging patients. 
The results of this work will lay the foundation for future studies 
that treat preoperative cognitive impairment as a risk factor and test 
interventions to improve geriatric surgical care and outcomes based on 
it. Examples might include discussion about the appropriateness or 
timing of surgery, preoperative consultation by a geriatrician, more 
careful titration of depth of general anesthesia (recently shown to 
reduce the risk of delirium),33,34 or triage to a specialized geriatric care 
unit postoperatively.31,35 Given the prevalence of likely cognitive 
impairment in our pilot study, preoperative cognitive screening 
promises to be an excellent low-cost, patient centered, high impact 
proposition for enhancing surgical outcomes in seniors.  
 
Objectives: 
Our overriding hypothesis is that preoperative cognitive impairment is a 
risk factor for poor surgical outcomes in seniors and that 
preoperative screening is superior to standard or systematic 
clinical processes for identifying at-risk patients. 
Objective 1. Assess the marginal benefit of structured preoperative 
cognitive screening relative to standard or systematic preoperative 
evaluation for identifying seniors with likely cognitive impairment.  

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Objective 2. Determine whether preoperative cognitive impairment 
predicts postoperative outcome.  
Objective 3. Determine whether other preoperative variables (mood, 
social support, history of depression, pain, and health and 
functional status) predict postoperative outcome.  
 
Subject Selection:  This project is designed as a prospective, single-
center observational study. The cohort will consist of 500 consenting 
subjects ≥ 70 years of age who present to the BWH Weiner Center for 
Preoperative Evaluation (CPE) prior to elective thoracic surgery 
(specifically, thoracoscopic lung resection, lobectomy, thoracotomy, or 
esophegectomy) or to neurological anterior, posterior cervical, 
thoraco, or lumbar spine surgery performed by neurosurgeons or 
orthopedic spine surgeons.  250 subjects undergoing thoracic surgery 
will be recruited and 500 subjects undergoing spine surgery will be 
recruited. These ages are chosen as significant clinical data 
demonstrate increased cognitive impairment in community dwelling 
elders. Eligibility criteria include: patients ≥ 70 years of age with an 
ASA physical status of I-III presenting for elective thoracic, or 
orthopedic anterior or posterior cervical, thoraco, or lumbar spine 
surgery. Exclusion criteria will include history of stroke (not including 
TIAs) or brain tumor, uncorrected vision or hearing impairment 
(unable to see pictures or read or hear instructions); limited use of the 
dominant hand (limited ability to draw); and or inability to speak, 
read, or understand English. 
 
An additional cohort of 50 patients aged 45-60 undergoing elective 
neurological posterior thoracolumbar spine surgery or orthopedic spine 
surgery with an ASA physical status of I-III will be recruited through 
the BWH Weiner Center for Preoperative Evaluation (CPE). Eligibility 
and exclusion criteria will be the same as the aged 70 and older 
cohort, barring age. The purpose of enrolling this small younger 
subject population is to compare biomarkers between the two groups.  
 
In addition to the 750 older (aged 70 and above) subjects undergoing 
elective surgery and 250 younger (aged 45-60) elective spine surgery 
patients, 10 young, healthy control subjects will be also be recruited. 
These participants will complete the memory testing, and undergo the 
blood draw procedure, to act as a comparison to the older surgical 
population. This gives a combined study total of 250 recruited 
patients. 
 
Subject Enrollment:  The Brigham and Women’s Hospital is the only 
study site.  

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Study staff will use the CPE computerized scheduling system, which is 
updated continuously in real time and captures relevant information 
such as age and procedure, to identify potential subjects. When 
patients check in with the receptionist in the CPE for their appointment 
they will be notified that they may be eligible to participate in a study 
in the CPE involving patients over the age of 70, or between the ages 
of 45 and 60. The receptionist will then provide them with a brochure 
(Attachment- Brochure) about the study that includes information 
about the purpose of the study, the risks to the patient, and the 
potential benefits to society. The patient will then be asked if they are 
willing to speak with one of the study investigators and only those 
patients that agree to speak with a study investigator will be 
approached. The staff member will then describe the goals and risks of 
the study in a quiet room in the PATC and ask the patient if they 
choose to participate; the staff member will also briefly and verbally 
screen for eligibility, asking the patient if he or she has a history of 
stroke, brain tumor, etc. After all questions have been answered and 
the patient has the opportunity to read the consent form, written 
consent will be obtained by one of the study investigators. 
 
Control subjects will be recruited from the community, and will be 
eligible if they are over the age of 18 and not scheduled for any 
elective surgeries. All eligible controls must be able to read and 
understand English, and be able to use their dominant hand.  
 
Study Procedures:   
After obtaining consent, study staff will gain information about the 
patient’s age and years of education. Study staff will administer 
standard instruments to assess mood (Geriatric Depression Scale-Short 
[GDS], a 15-item self-report questionnaire, and the Beck Anxiety 
Inventory [BAI]), The Amsterdam Preoperative Anxiety and Information 
Scale [APAIS], a brief, 6-item self-report questionnaire), social support 
(MOS Social Support Survey, a 12-item self-report questionnaire), pain 
(the Brief Pain Inventory Short-Form), frailty (the FRAIL scale assessing 
fatigue, resistance, ambulation, illness, and loss of weight), a risk 
assessment prior to surgery (MEDIA) measuring previous difficulties 
with memory, episodes of confusion, and cognitive enhancing 
medications, physical activity (the International Physical Activity 
Questionnaire – Short Form), and health and functional status (basic 
and instrumental activities of daily living [ADLs and IADLs, RAND 36-
SF, and the WHODAS respectively]). The World Health Organization 
Disability Assessment Schedule 2.0 (WHODAS) is an alternative to the 
SF36 to measure physical health and disability. Past diagnosis of 

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depression and pain noted on the patient’s preoperative evaluation form 
will be recorded, as well as past history of delirium or other post-
anesthetic complications, use of hearing and/or hearing aids, and 
medical comorbidites. In addition, patients will be asked if they’ve had 
a fall within the last 6 months, whether they’ve been evaluated for a 
change in memory or thinking, who accompanied them to their 
appointment, their employment status and their living situation (alone, 
institutionalized, living with family members) in a patient survey. The 
study staff will also administer the MiniCog, a simple cognitive screening 
tool that takes just 2-4 min to complete and has little or no education, 
language, or race bias. In addition, the Animal Fluency test will be 
administered, which is a short cognitive screen that takes one minute 
to complete. Patients will also complete the self-report cognitive 
assessment CANTAB Insight Cognitive Exam, using an iPad developed 
by Cambridge Cognition. This 10 minute assessment measures cognitive 
health on five axes: executive function, processing speed, attention, 
working memory, and episodic memory through three cognitive tests: 
Matching Patterns, Working Memory, and Pairs Associates Learning 
Tests. Other measures of cognitive impairment will be obtained by study 
staff through: documentation on the patient’s standard preoperative 
form, patient or informant report of diagnosis or evaluation for cognitive 
impairment or memory concerns, and systematic medical record review. 
Each enrolled patient will receive a business card listing the 
investigators’ contact information and be advised to expect a follow up 
telephone call 6 months and 1 year after surgery to verify data elements 
and reassess functional outcome. 
 
During their routine preoperative blood draw the phlebotomist will be 
provided with one 10mL heparinized blood tube, one 5mL heparinized 
blood tube and one 5mL non heparinized blood tube labeled with only 
the patient’s study ID number that will be returned to the investigative 
team and processed within 30 minutes of the blood draw. If the 
phlebotomist is not able to obtain a sample during the patient’s 
preoperative appointment, a sample will be drawn by a study staff 
member trained by one of the anesthesiologists, or a nursing or 
physician member of the anesthesiology team prior to incision instead. 
200 uL of this sample will be sent to a Partner’s Core Facility for 
analysis of the APOE gene, specifically for the e4 allele which has been 
shown to be linked in the development of late-onset Alzheimer’s and 
delirium. The presence of the E4 allele will be included in our 
multivariate analysis for the development of postoperative delirium. 
Genetic results will not be shared with participants, nor entered into 
the medical record. 20mL of blood will also be obtained on 
postoperative days 1-3 by a study staff member trained by one of the 

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anesthesiologists, or a nursing or physician member of the 
anesthesiology team. Total, the proposed collection is 80mL. 
However, the additional 60mL blood sample on post-op days 1-3 
will only be collected if the Hematocrit level is 0.25 or higher. Briefly, 
half of the sample would be spun down and plasma harvested and 
stored at -80 degrees C and when an adequate sample size obtained 
used to measure inflammatory cytokines by ELISA. From the whole 
blood, we will isolate and purify monocytes using magnetic activated 
cell sorting (MACS), and then further isolate total RNA from the 
monocytes, which will be analyzed using RNA-seq. This analysis will 
capture the complexity of monocytes at different stages of the 
perioperative state by providing a comprehensive, genome-wide 
sampling of cell types. The remainder of the sample will be divided into 
1-ml aliquots and incubated at 37°C for 15 min with phosphate-
buffered saline (PBS) (control), 100 ng/ml interleukin (IL)-6, 100 
ng/ml IL-10, or a combination of 100 ng/mlIL-2 and 2 ng/ml 
granulocyte macrophage colony-stimulating factor, or 1g/ml 
lipopolysaccharide. Blood samples will be resuspended in 1.4 ml 
stabilizing buffer and incubated for 10 min at room temperature for 
fixation in PFA, cooled to 4C, and stored at 80C until further 
processing for flow cytometry to determine the immune response of 
the white blood cells to a ex-vivo immune challenge and whether these 
correlate with Mini-Cog score or the development of delirium. 
We will be sending de-identified (containing only subject ID and 
whether they were in the young or old cohort) blood samples from the 
proposed research to the Broad Institute and OLINK for RNA-seq 
analysis and protein analysis, respectively. We have fee-for-service 
agreements with both services. All samples and data collected for this 
research will be obtained with IRB approval and informed consent of 
study participants to sharing de-identified data. We will transfer de-
identified blood samples of the patients enrolled in the study. We will 
then receive analyses in the form of raw data through PI-controlled 
password encrypted data files. The identities of research participants 
will not be disclosed to the repository. We will take appropriate steps 
to de-identify datasets according to the HIPAA privacy law. 
https://privacyruleandresearch.nih.gov/pr_08.asp. The raw data 
collected from the Broad Institute and OLINK will then be further 
analyzed by research staff listed on this protocol.  
Delirium will be assessed prospectively twice per day (early 
afternoon, early afternoon) on postoperative days 1, 2, and 3 by a 
trained study team member using the Confusion Assessment Method 
[CAM-3D] and the 4AT. Delirium is most common on postoperative 
days 1-3 and both the CAM and the 4AT are well-validated measures 
of delirium in surgical patients. For patients that are in the Intensive 

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Care Unit (ICU) postoperatively, the Confusion Assessment Method for 
the ICU (CAM-ICU) will be administered prospectively twice per day on 
postoperative days 1, 2, and 3 by a trained study team member 
(Attachment-CAM-ICU). For functional status, the WHODAS will be 
administered 6-12 months postoperatively either by personnel in the 
surgeon’s office as part of routine follow up or by study staff or by 
telephone. We will also collect information on secondary outcomes 
including duration of PATC visit, presence of an advanced directive, 
whether they had surgical procedure, time to PACU discharge, 
discharge to place other than home (rehabilitation, skilled nursing 
facility), hospital length of stay (LOS), in hospital complications, 
perioperative variables including drugs administered, pain scores and 
pain medication administration, BIS, estimated blood loss, blood 
transfusions, fluid administered, blood pressure, oxygen saturation, 
30-day reoperation or readmission rate, and 30-day and 1-year 
mortality. These outcomes are recorded in the medical record, the 
BWH Balanced Scorecard, an electronic database of all hospitalized 
patients that tabulates 31 elements of the hospital event, or the BWH 
Research Patient Database Enhanced Query. Data will also be 
confirmed by a follow up telephone interview. Thirty day and 1 year 
mortality will be recorded. 
 
Controls will be asked to complete the MiniCog, as well as a blood 
sample comprising of one 10mL heparinized blood tube, one 5mL 
heparinized blood tube and one 5mL non heparinized blood tube. 
 
Data Analysis:  As in our pilot study, we will define “likely cognitive 
impairment” as a score ≤ 2 on the MiniCog; while we are aware it is by 
no means a gold standard, it is based on a well validated cutoff that 
serves our purpose of identifying patients who may need special 
approaches during the perioperative period. All analyses will be 
repeated in the subset of individuals with the greatest degree of 
cognitive impairment based upon a MiniCog score of (0-1) in order to 
understand why these individuals were not identified as cognitively 
impaired. We will first test the sensitivity of standard procedures 
compared to systematic procedures with MiniCog defined impairment 
or severe impairment. We will also compare sensitivity and specificity 
of the standard vs. systematic approach, and vs. the published 
sensitivity of 75% in comparable populations. As a secondary 
outcome, we will try to understand the full relationship among our four 
assessments, for instance whether systematic chart review and 
patient/informant reports detect individuals not detected by standard 
MiniCog cutoffs, as such individuals would be important to include as 
part of a broad “impairment” outcome for Aim 2 and consider in 

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subsequent work for special care in the perioperative period. Similarly, 
if we see patients who have received a formal evaluation of cognitive 
status in a memory clinic, by a primary care physician, or 
neuropsychological testing, we will try to understand qualitatively how 
MiniCog scores compare to such evaluations. Another secondary 
outcome will be how well patient/informant report can augment chart 
review when the patient does not have a primary care physician within 
our network. Differences between sensitivities and specificities will be 
compared using standard methods using confidence intervals. 
We will use logistic regression with any delirium as the outcome 
and cognitive impairment as defined by the MiniCog cutoff (or level of 
cognitive function as defined by the ordinal MiniCog score, modeled as 
best fits the data) in univariate analyses and in multivariate models 
adjusting for demographics (age, gender, education), baseline 
functional and medical covariates (ASA functional status, METs, 
frailty). Analogous analyses for our secondary outcomes will use 
logistic, linear, or Cox proportional hazards models to assess the 
relationship of MiniCog scores to these outcomes. In univariate 
analyses, we will compare change in WHODAS in MiniCog-impaired vs. 
unimpaired patients using Wilcoxon U test and with ordinal MiniCog 
score using Spearman rank order correlation. Multivariate analyses will 
model change in WHODAS (ranked or transformed for best model fit) 
as a function of MiniCog impairment status (or ordinal value as above), 
controlling for age, gender, education, comorbidity index, and frailty. 
In exploratory analyses, patients with and without postoperative 
delirium will be analyzed separately and compared. 
 
Assays performed using blood collected between from the 
current study will be analyzed in the grant Circulating Extracellular 
Vesicles as Biomarkers of Postoperative Delirium (grant submission 
number 1R21 AG061696-01). Co-investigator Gregory Crosby, MD, is 
the PI of the above grant; no changes to the current protocol will be 
made for this analysis.  
 
Risks and Discomforts:   
Overall, this study poses low risks for the subjects. The sources of risk 
are of two types in this study, 1) participation in the interviews and 
cognitive test and 2) the risk of breach of confidential information. The 
first “risk” of the study is the time necessary to participate in the study 
assessments. However, in our pilot study, patients viewed the 
interactions with the research staff as very positive and enjoyable. It is 
possible that some of the assessments may pose the risk of fatigue or 
emotional distress. Should a patient become tired or distraught, the 
interview will be halted. A related “risk” of participation is the potential 
breach of confidentiality and privacy of the Protected Health 

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Information. Methods to reduce this risk include all investigators 
undergoing extensive training in general principles of informed 
consent, confidentiality, and administering research instruments in a 
humane, reliable, and valid manner. All data will be deposited into 
REDCap, a secure, web-based application for research storage and 
used for research purposes. There will be no interventions as a result 
of this study. The data gathered will have no effect on the care that 
the patient is to receive. Both the CPE providers preoperatively 
evaluating the patient and the surgeon will not have access to the 
result of the baseline testing.  
 
Potential Benefits:   
This study is being performed to advance medical knowledge. There 
are no expected benefits to individual subjects participating in the 
study but it will help advance understanding of how preoperative 
cognitive performance affects perioperative outcomes in older patients. 
This study has the potential to aid and improve decision-making by 
physicians and older patients in the future if they reveal a relationship 
between poor preoperative cognitive status and adverse cognitive and 
functional postoperative outcomes in older patients.  
 
Monitoring and Quality Assurance: 
Regardless of monitoring plans, the principal investigator is ultimately 
responsible for ensuring that the study is conducted at his/her 
investigative site in accordance with the IRB-approved protocol and 
applicable regulations and requirements of the IRB. 
 
The Principal Investigator or a member of the investigative team will 
monitor each subject at this single site, and will review the accuracy 
and completeness of all testing, source documents and informed 
consent. 
 
There will be no Data Safety Monitoring Board as the results of these 
studies will have no impact on the care that patients receive.  The 
outcomes of the study are intended to be published in a peer-reviewed 
manuscript to document whether preoperative cognitive screening is a 
risk factor for adverse postoperative outcomes and the feasibility and 
cost of preoperative cognitive stratification in the preadmission testing 
center.  All adverse events will be reported to the Partners the Human 
Research Committee (HRC) in accordance HRC guidelines.  A 24-
hour/7-day telephone or pager number will be provided for contacting 
the licensed physician investigator for this purpose. 
 

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The research staff will monitor all subjects during the course of study 
involvement for evidence of any adverse events such as unexpected 
stress and the testing discontinued and the incident reported to 
Partners the Human Research Committee within 24 hours of local 
event awareness (but no later than the next business day). The report 
will include a complete description of the event, use of all concomitant 
medications, and the local investigator’s assessment of causality of the 
adverse event.  Follow-up evaluations will be done until there is 
resolution of the adverse events, which are unlikely as this protocol is 
non-invasive   
 
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