NIH Explanatory/Developmental Research Grant Program: Preoperative Cognitive Screening in Older Surgical Patients: Feasibility and Utility for Predicting Morbidity
Conditions: Cognitive Impairment
Sponsor: Brigham and Women's Hospital

Study Protocol and Statistical Analysis Plan:  
Preoperative Cognitive Screening in Older Surgical Patients Utility for Predicting Morbidity, 
NCT 02598050, Document date 03/01/2021  
 

Study Protocol 
Subject Selection: This project is designed as a prospective, single-center observational study. 
The cohort will consist of 250 consenting subjects ≥ 65 years of age who present to the BWH 
Weiner Center for Preoperative Evaluation (CPE) prior to elective lower extremity joint 
replacement surgery. These surgeries are selected because they are common in this age group, 
associated with significant morbidity, and along with dementia are considered a priority area 
(bone and joint conditions) by AHRQ. These ages are chosen as significant clinical data 
demonstrate increased cognitive impairment in community dwelling elders. Eligibility criteria 
include: patients ≥ 65 years of age with an ASA physical status of I-IV presenting for elective 
joint replacement or non-cancer spine surgery. Exclusion criteria will include planned ICU 
admission postoperatively, history of stroke 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. Subject 
Enrollment: The Brigham and Women’s Hospital is the only study site. 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 
(and their surrogate) may be eligible to participate in a study in the CPE involving patients over 
the age of 65 or between the ages of 45-60. The receptionist will then provide them with a 
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. Patients with known cognitive impairment will be included in 
the study to determine whether this information is included in the preoperative evaluation form. 
They will sign their own consent if they are capable and going to sign their surgical procedure 
consent. In the event that the patient is not capable of signing their own consent a surrogate will 
be asked to provide consent with assent from the patient. In our prior studies with similar patient 
populations less than 1% had documented cognitive impairment. The staff member will then 
describe the goals and risks of the study in a quiet room in the PATC and ask the patient (and 
their surrogate where appropriate) if they choose to participate. 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. 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), social support (MOS Social Support Survey, a 12-item selfreport 
questionnaire), alcohol consumption (Alcohol Use Disorders Identification Test—Consumption 
[AUDIT-C], a 3-item self-report questionnaire), and health and functional status (basic and 
instrumental activities of daily living [ADLs and IADLs, respectively, and the WHODAS]).The 
World Health Organization Disability Assessment Schedule 2.0 (WHODAS) is an alternative to 
the SF36 to measure physical health and disability. The Brief Pain Inventory (Short-Form) will 
be administered to assess pain before surgery. Grip strength will be measured with a JAMAR 
hand dynamometer as an index of frailty. 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. 
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. 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. 20mL of blood will also be obtained after surgery 
in the PACU and also on postoperative day 1 by a study staff member trained by one of the 
anesthesiologists, or a nursing or physician member of the anesthesiology team. Total, the 
proposed collection is 60mL. However, the additional 20mL blood sample on post-op day 1 will 
only be collected if the Hematocrit level is 0.30 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. The remainder of the sample will 
be divided into 1-ml aliquots and incubated at 37°C for 15 min with phosphatebuffered saline 
(PBS) (control), 100 ng/ml interleukin (IL)-6, 100 ng/ml IL10, 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. Each 
enrolled patient will receive a business card listing the investigators’ contact information and be 
advised to expect a follow up telephone call prior to surgery to assess cognitive function and at 6 
months and 1 year after surgery to verify data elements and reassess functional outcome. 
Delirium will be assessed prospectively twice per day (early afternoon, early evening) on 
postoperative days 1, 2, and 3 by a trained study team member using the Confusion Assessment 
Method [CAM]. Delirium is most common on postoperative days 1-3. For functional status, the 
WHODAS will be administered 6-12 months postoperatively, along with the Geriatric 
Depression Scale to assess mood, 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, 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.  
 
Statistical Analysis Plan 

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 
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, Charlson 
Comorbidity Index, 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 from the current study will be analyzed in the 
grant “Circulating Extracellular Vesicles as Biomarkers of Postoperative Delirium” (grant 
submission number 1R21 AG061696-01). The grant has now received funding. Gregory Crosby, 
MD, is the PI of the above grant; no changes to the current protocol will be made for this 
analysis. As a secondary analysis using variables collected during the course of the open 
enrollment phase of the study, a machine learning algorithm will be designed, to attempt to 
create a meaningful predictive model of postoperative delirium detection. This secondary use of 
data will explore the value of machine learning in anesthesiology, and its potential in predicting 
postoperative delirium.