Successful Aging after Elective Surgery II: Study Cohort Description

Abstract

Background:

The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer’s disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID-19 pandemic, and lay the foundation for future work using this cohort.

Methods:

SAGES II is a prospective observational cohort study of community-dwelling adults age 65 and older undergoing major non-cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID-19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality.

Results:

420 participants were enrolled with a mean (standard deviation) age 73.4 (5.6) years, including 14% minority participants. Eighty-eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID-19 pandemic, which required use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1 month follow-up; nearly 90% of enrolled participants completed interviews through 6 month follow-up.

Conclusion:

While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through application of novel biomarkers—including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource.

INTRODUCTION

Delirium, a clinical disorder characterized by an acute decline in attention and cognition, occurs with an incidence of 12–51% after non-cardiac surgery.¹ Postoperative delirium is the most frequent complication following surgery, but is often unrecognized in older adults.² Precipitating factors for delirium are often preventable, emphasizing the importance of determining risk factors and pathways to improve early prevention and intervention.^3,4

Delirium’s adverse impact is profound including functional decline, accelerated cognitive decline, prolonged hospitalization, and higher healthcare costs (approximately $32.9 billion nationally per year).^5,6 The development of delirium serves as a marker of brain vulnerability, and postoperative delirium has been associated with 40% accelerated cognitive decline 72 months following surgery.^6,7 However, the pathophysiological pathways linking delirium to dementia remain unclear.⁸

We previously conducted the Successful Aging after Elective Surgery (SAGES I) Study following a cohort of over 560 older adults undergoing surgery.^9,10 This innovative study built the foundation for the current SAGES II study by examining the interrelationship between delirium and long-term cognitive decline, and elucidating potential biomarkers and explanatory pathways.¹¹ The SAGES II study expands our exploration by probing more deeply into the relationship between delirium and Alzheimer’s disease and related dementias (AD/ADRD), through the use of novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. While the study design and methods for SAGES II have been previously described,¹² the goal of this paper is to detail for the first time the baseline characteristics of the enrolled cohort, delineate the procedures used to optimize data quality, and describe the study modifications that allowed complete data collection despite the COVID-19 pandemic, laying the foundation for future work using this cohort.

METHODS

Overview and Study Population

The SAGES II study is an ongoing five-year prospective observational cohort study of 420 older adults age 65 and older undergoing major non-cardiac surgery enrolled between April 1, 2019, and June 13, 2022. The study design and eligibility criteria have been previously described.¹² Eligible participants were English speaking, and either age 65 and older and undergoing total knee or hip replacements, or age 70 and older undergoing other major non-cardiac surgeries at one of three Harvard-affiliated academic medical centers. Written informed consent was obtained from all study participants according to procedures approved by the Institutional Review Board of Beth Israel Deaconess Medical Center, with reliance agreements from Brigham and Women’s Hospital/Brigham and Women’s Faulkner Hospital, and Hebrew SeniorLife.

Recruitment

Potential eligible patients were identified through a daily review of the operating room schedules, and contacted by study staff to assess interest. The team received training and spent additional time recruiting under-represented minorities to increase diverse representation. A participant was considered enrolled after the completion of surgery. Figure 1 details the flow of enrollment. The COVID-19 pandemic altered the enrollment timeline due to reduction in scheduled elective surgeries during surges.

Figure 1.

Summary of enrollment

Data Collection Protocol

Preoperative Baseline and Postoperative Follow-up Interviews

A 90-minute baseline interview was conducted prior to index surgery and 45-minute follow-up interviews were conducted at 1, 2, 6, 12, and 18 months after surgery. Caregiver proxies were contacted at baseline and every 6 months after surgery. Specific assessments have been described previously and are listed in Supplement 1.¹² Briefly, assessments collected detailed information on cognitive and physical functioning, self-reported health, hearing and vision impairment. The General Cognitive Performance (GCP)¹³ is a weighted composite summary measure, which synthesizes the results from our comprehensive neuropsychological test battery, scaled 0–100, with general population mean 50 ± 10.

During COVID-19 surges and based on participant comfort, in-home assessments were conducted by videoconference using a secure Zoom platform on an encrypted iPad (Figure 2). All necessary equipment was provided by research assistants through a contactless drop-off before the interview. Frailty, vision, and hearing were assessed by self-report during remote assessments (Supplement 2).¹⁴ When video interviews were not possible, telephone interviews were completed.

Figure 2.

Sequence and timeline of COVID-19 procedure modifications

Abbreviations: DC, discharge; PAT, pre-admission testing; CSF, cerebrospinal fluid; TMS-EEG, transcranial magnetic stimulation/electroencephalography; MRI, magnetic resonance imaging; PET, positron emission tomography.

Index Hospitalization: Daily Delirium Assessments

During hospitalization for surgery, delirium was assessed once daily from postoperative day 1 (POD1) through discharge by interviews with trained research assistants. If patients were discharged on the surgical day (POD0) or POD1, in-home assessments were conducted, which were converted to telephone assessments during the COVID-19 pandemic. If a participant was delirium positive, interviews were completed until there were two consecutive delirium-negative days.

Delirium presence was defined by meeting Confusion Assessment Method (CAM)¹⁵ criteria on one or more hospital daily interviews, or by the standardized chart review method¹⁶ detecting delirium at any point during the hospitalization. The CAM is a 10-item standardized delirium assessment with sensitivity of 94%, specificity of 89%,¹⁷ and inter-rater reliability of 0.70–1.00. The CAM was rated based on observations during interviews and performance on cognitive testing (abbreviated Montreal Cognitive Assessment, Months of the Year Backwards, Days of the Week Backwards), and an abbreviated Delirium Symptom Interview.¹⁸ Delirium severity was measured using the CAM-Severity (CAM-S)¹⁹ score based on the long-form CAM (0–19, 19 = most severe).

Index Hospitalization: Medical Record Review

At hospital discharge, study clinicians reviewed the electronic health record to collect information listed in Supplement 1. The chart review included a validated chart-based delirium tool¹⁶ and all diagnoses were adjudicated by an expert panel.

Post-Hospital Outcomes

Information on rehospitalizations and nursing home stays was obtained during telephone interviews with participants every three months and caregivers every 6 months.

Biomarkers and Imaging

Blood samples for biomarker analysis were collected at four time points (Preoperative, morning of POD1 and POD2, and 1-month follow-up). Anesthesiologists collected cerebrospinal fluid (CSF) during the induction of spinal anesthesia. When CSF collection was not possible, participants had the option to complete an Amyloid positron emission tomography (PET) scan 1 month or more after their surgery. During baseline interviews, participants were informed about magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS)/electroencephalography (EEG) as optional additions to the study. Participants who were not eligible or not interested in TMS were offered the option to have resting-state EEG instead.

Data Management and Quality

Rigorous data quality procedures were implemented as used previously for SAGES I to cover four dimensions of data quality assurance, including completeness, consistency, accuracy, and timeliness.¹⁰

Interviews

All research assistants underwent at least four weeks of didactic training and standardization before conducting interviews independently. Interrater reliability assessments were completed initially then semi-annually throughout the study, and results were used to inform areas needed for further standardization.¹² Questions related to coding were discussed at weekly team meetings to ensure standardization and consensus among study staff. In addition, all assessments were rechecked by peers to ensure accuracy and completeness.

Other Study Procedures

Specimens were stored in aliquots with unique identifiers. Data was entered into a Research Electronic Data Capture (REDCap^®)²⁰ database, including date and time drawn, time processed, volume, and sample quality. A detailed R-statistical software linked to the REDCap database provided an updated manifest that was crosschecked regularly to keep track of sample collection and organization within the freezer biorepository.

Data acquired from MRI, PET scans, and TMS-EEG were stored on secure, password protected private servers only accessible to authorized research personnel. Patient identifiers were stored separately using the unique study IDs.

Data Management

The electronic data capture system was programmed with automated data quality and error checking algorithms, which provided automatic warning messages when questions were left blank or out-of-range values were entered. Automated reminders were sent to study staff when follow-up interviews were due within pre-defined windows.

RESULTS

Enrollment

Of 1,760 individuals eligible for telephone screening, 890 (50%) declined to participate with the most common reasons cited as concerns about the uncertainty of the pandemic, and being overwhelmed before going for surgery. The patients who did not complete telephone screening either did not respond, told the team to call back later, or were unable to be contacted by the team due to limited staffing capacity. There were 476 baseline assessments completed: 29 consented but did not enroll and 27 became late ineligible (such as having their surgery canceled or converted to a non-eligible procedure), resulting in 420 individuals enrolled (Figure 1). The response rate, the percentage of estimated eligible participants who were enrolled calculated using a published approach,^10,21 was 74%. Due to the COVID-19 pandemic, nine patients who had already completed baseline assessments had their elective surgeries canceled completely.

Cohort Characteristics

The demographic and baseline characteristics of the cohort are shown in Table 1. The average (standard deviation; SD) age was 73.4 (5.6) years; 65% of participants were female, and 86% were White and Non-Hispanic. The mean (SD) number of years of education was 16.3 (2.7), which is equivalent to four years of college. There were 69% living with someone else, and 57% were married. Eighty-eight percent of participants had either total knee or hip replacements, and 210 individuals (50%) had total knee replacements. The cohort also had a high baseline cognitive function, with an average General Cognitive Performance (GCP) of 61, which is 1 standard deviation above the mean of an age-matched general U.S. population. The Functional Activities Questionnaire (FAQ) showed a high level of independence with instrumental activities of daily living, with a mean score of 1.3 (range 0–30, 30 dependent). The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function T score was 40.3 (SD 7.1), which is one standard deviation below the general U.S. population mean of 50. Frailty measures showed that 37% of participants were robust, 50% were prefrail, and 13% were frail.

Table 1.

Characteristics of study cohort (N=420)

	Mean ± SD or count (%)
Age	73.4 ± 5.6
Female	271 (65)
Race
Asian	5 (1)
Black or African American	37 (9)
White	369 (88)
More than one race	9 (2)
Hispanic ethnicity	8 (2)
Education, years	16.3 ± 2.7
Married	241 (57)
Living alone	130 (31)
Surgery Type
Total knee replacement	210 (50)
Total hip replacement	160 (38)
Spine	27 (6)
General	10 (2)
Vascular	3 (1)
Urology	9 (2)
Cervical	1 (0)
Anesthesia Type
General alone	91 (22)
Spinal alone	317 (75)
Combination	12 (3)
Visual Impairmenta	12 (3)
Hearing Impairmentb	101 (24)
General Cognitive Performance score13 (range 0–100)	61.0 ± 8.1
Charlson Comorbidity Index score25	0.9 ± 1.4
Geriatric Depression Scale-15 score26 (range 0–15)	2.5 ± 2.3
Baseline Functioning
PROMIS27 Bank Physical Function T scorec	40.3 ± 7.1
FAQ score28 (range 0–30, 30 worst)	1.3 ± 2.5
Postoperative Acute Physiology and Chronic Health Evaluation II (APACHE II) Score29 (range 0–71)	11.3 ± 2.9
12-Item Short Form Survey30 (SF-12)c
Physical	33.5 ± 9.0
Mental	51.1 ± 8.4
Frailty
Robust	155 (37)
Prefrail	209 (50)
Frail	56 (13)

Abbreviations: PROMIS, Patient-Reported Outcomes Measurement Information System; FAQ, Functional Activities Questionnaire

^aVision Impairment is defined as <20/70 corrected binocular vision or self-reported

^bHearing Impairment is defined as <6/12 on Whisper test of self-reported

^cPROMIS and SF-12 are T scores with a mean of 50 and standard deviation of 10 in general U.S. populations

Degree of completeness

Interviews.

POD1 and POD2 delirium assessments were completed for 98% of participants (Supplement 3). For postoperative delirium assessments, 73% were conducted in-person and 27% were telephone assessments. Reasons for missing hospital delirium assessments included participant refusal, unavailability due to clinical care, or missed phone calls for assessments after discharge. The original cohort (n=420) was reduced by 26 participants at 1 month follow-up due to 1 drop out, 2 deaths, and 23 refusals or unobtainable interviews. This was further reduced at 2 months and 6 months to include 45 refusals or unobtainable interviews. Follow-up is ongoing for 12 and 18 month interviews, and any initial refusals or unobtainable participants are still being tracked to complete future interviews. Reasons for refusal or unobtainable interviews included declining health, time constraints, or increased family responsibilities. Of 1,574 total interviews up to 6 months follow-up, 64% were completed in-person, 15% were by video, and 21% were by telephone.

Blood and CSF Collection.

Blood was collected for 99% of participants at baseline, 91% on any postoperative day, and 74% at one month. Reasons for missing samples included refusal, difficulty drawing blood, and lack of lab processing availability. After the start of COVID-19, home blood draws were not allowed so if a participant was discharged before POD2 or had a virtual 1-month appointment, the blood was not collected. 39% of participants were discharged before POD2 prior to March 2020 when the COVID-19 pandemic started, whereas 48% of participants were discharged before POD2 after March 2020. CSF was collected for 275 (87%) of the 317 patients with spinal anesthesia. Samples were not collected due to slow CSF flow or clinical time constraints.

Specialized Study Procedures.

For those without CSF, 49 participants completed amyloid PET scans. In addition, 106 participants completed MRI scans before surgery and 90 completed the TMS-EEG procedure. At 2-months postoperative, 69 of those completed a second TMS-EEG procedure, and 44 completed a third 12-month follow-up TMS-EEG procedure.

DISCUSSION

This paper describes the successful completion of enrollment of the SAGES II cohort, despite the challenges posed by the COVID-19 pandemic. This is the first comprehensive cohort description for this innovative study, designed to examine the relationship between delirium and dementia through the application of novel biomarkers—including fluid (plasma and CSF), imaging, and electrophysiological markers. The cohort included community-dwelling older adults who were highly educated and had generally high cognitive functioning, about 1 standard deviation above the age-matched U.S. population mean. The majority of participants underwent total knee or hip replacements, with half of the cohort undergoing total knee replacements. About one-quarter of individuals met criteria for hearing impairment, which has been previously shown to be a risk factor for developing delirium.²² Participants were highly independent in instrumental activities of daily living at baseline, as shown by the low FAQ mean of 1.3 with a score of 30 being the most dependent. Overall, almost two-thirds of participants were considered at least pre-frail (13% frail and 50% pre-frail). This is similar to a nationally representative study of community-dwelling adults age 65 and older, which found that 15% are frail and 45% are prefrail.²³ Prior studies have shown that frailty is associated with postoperative delirium in older adults.²⁴

With comprehensive preoperative and follow-up assessments, the SAGES II cohort provides valuable information not only about incident delirium and its outcomes, but also about the long-term cognitive and physical functioning of community-dwelling older adults following surgery. The strengths of the study include the high quality data collection protocols and relatively low missing data despite challenges faced by the study during COVID-19. While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes (e.g., cognitive and physical functioning, frailty, depression, quality of life) up to 18 months after major surgery, along with novel biomarker analysis and substudies of participants with MRI, TMS-EEG, and PET scans. In addition, the study team received specific training and dedicated additional time to recruit under-represented minorities with the goal of increasing the racial and ethnic diversity of the cohort. Due to these efforts, there was diverse representation in 14% of the sample, an increase of 6% from SAGES I.¹⁰

Despite conducting the majority of this study during the COVID-19 pandemic, the study leaders rapidly implemented study adaptations that allowed for minimal disruptions in data collection. The only period with no enrollment was between March 15, 2020 and June 1, 2020 during a state-wide COVID-19 lockdown, with slower enrollment at 3 additional time points due to pandemic surges (Figure 2). The recruitment and retention of participants during the pandemic required maximal flexibility to adapt to surgery cancellations and infection control protocols, while adhering to both state and hospital policies. Patient refusals increased from 36% before March 2020 to 56% afterwards largely related to concerns or uncertainty due to the pandemic. The study team also had to increase their effort and time during the pandemic, transporting video equipment and conducting everything virtually or contact-free; this resulted in staff not being available to complete all the recruitment calls and patient interviews for the study. The research team initially transitioned to telephone interviews, and then to video interviews, which allowed for neuropsychological testing that more closely matched the in-person interviews. Validation of the alternative assessment methods is currently underway to determine the inter-correlation between the interview modes.

Several limitations should be mentioned. First, this study was conducted in a single geographical area with a highly educated cohort that was healthy enough to undergo elective surgery. Therefore, generalizability may be limited and findings may need to be replicated in other settings. Second, the age cut-off was adjusted downwards (65 rather than 70 years) to enhance enrollment, resulting in the mean age of the cohort being lower than anticipated. This change may have compromised the overall power of the study to detect age-related outcomes such as delirium, cognitive and functional decline, and dementia.

CONCLUSION

This paper serves as an important reference for future studies using the SAGES II cohort. Future analysis of this cohort will help to advance our understanding of delirium and determine the multifactorial risk factors for delirium, while helping to advance our fundamental pathophysiological understanding of delirium. Ultimately, this study will provide important groundwork for future clinical trials to test perioperative interventions for older persons undergoing surgery to reduce the burden of delirium.

Supplementary Material

Supinfo

Supplementary Table S1: Description of study variables and timepoints of assessment

Supplementary Table S2: SAGES II COVID-19 adaptations

Supplementary Table S3. Data completeness through 6 month follow-up (N=420)

Supplementary References

Key points:

• The SAGES II study is a prospective observational cohort study of 420 community-dwelling older adults undergoing major non-cardiac surgery examining the inter-relationship between delirium and long-term cognitive decline.

• Despite enrolling through COVID-19, the study had high data completion rates with almost 90% of participants completing interviews through at least 6 months follow-up and ongoing up to 18 months.

• This paper highlights the novelty of the SAGES II study cohort, with higher diversity than SAGES I, and collection of comprehensive health outcomes with novel biomarker and imaging to investigate postoperative delirium.

Why does this paper matter?

The SAGES II study is an important contribution to longitudinal studies of older adults, and provides unique insight into health outcomes of older adults following major non-cardiac surgery. This paper will serve as an important reference for future analysis of this cohort through the description of the baseline physical and cognitive functioning, data completion rates, and COVID-19 protocol modification details.

SAGES II Study Group

Overall Principal Investigator:

Sharon K. Inouye, MD, MPH (Overall PI, Administrative Core, Project 1; HSL, BIDMC, HMS).

Project and Core Leaders:

Bradford Dickerson, MD (Project 3; MGH, HMS); Richard Jones, ScD (Data Core, Project 4; Brown University); Towia Libermann, PhD (Project 2, BIDMC, HMS); Edward R. Marcantonio, MD, SM (Overall Co-PI, Epidemiology Core, Project 2; BIDMC, HMS), Alvaro Pascual-Leone, MD, PhD (Project 5, HSL, HMS); Mouhsin Shafi, MD, PhD (Project 5, HMS, BIDMC). Thomas Travison, PhD (Data Core, HSL, HMS);

Executive Committee:

Michele Cavallari, MD, PhD (BWH); Simon T. Dillon, PhD (HMS, BIDMC); Tamara Fong, MD, PhD (HSL, BIDMC, HMS,); Eva M. Schmitt, PhD (Overall Project Director, HSL); Alexandra Touroutoglou, PhD (MGH, HMS).

Other Co-investigators:

David Alsop, PhD (Project 3; BIDMC, HMS); Steven Arnold, MD, (MGH, HMS); Tammy Hshieh, MD, MPH (BWH, HMS); Yuta Katsumi, PhD (MGH), Long Ngo, PhD (BIDMC, HMS); Jessica Ross, PhD (BIDMC), Sarinnapha Vasunilashorn, PhD (HMS, BIDMC, HMS), Pia Webb Kivisakk, MD, PhD (MGH, HMS).

Clinical Consensus Panel:

Franchesca Arias, PhD (BIDMC, HMS); Eyal Kimchi, MD (MGH, HMS), Eran Metzger, MD, (HSL, BIDMC, HMS); Jason Strauss, MD (Cambridge Health Alliance); Bonnie Wong, PhD (MGH, HMS, MGH).

Surgical and Anesthesia Leaders:

Brandon Earp, MD (BWFH, HMS); Lisa Kunze, MD (HMS, BIDMC); Jeffrey Lange, MD (BWH, HMS); Marc Schermerhorn, MD (HMS, BIDMC); David Shaff, MD (BWFH, HMS); Kamen Vlassakov, MD (BWH, HMS).

Epidemiology Core:

Maja Burch (BIDMC) Rejoice Dhliwayo (BIDMC), Amanda Gallagher (HSL); Grace Going (HSL), Yonah Joffe (HSL), Shu Jing Lian (BIDMC), Julianna Liu (HSL); Molly Mackler (HSL); Madeleine Martine (HSL); Gina Michael (BIDMC), Nancy Otaluka (BIDMC), Kerry Palihnich (BIDMC), Fotini Papadopoulou (BIDMC), Lauren Phung (BIDMC), Anna Pleet (HSL); Christopher Ramirez, (MGH); Andrei Rodionov, PhD (BIDMC), Louis Shaevel (BIDMC), Hannah Shanes (HSL), Meghan Shanahan (HSL), Stephanie Waldman (BIDMC), Peter Wang (BIDMC), Michelle Ward (BIDMC), Karen Weng (HSL), Guoquan Xu (HSL).

Data Management and Statistical Analysis Core:

Yun Gou, MA (HSL); Benjamin Helfand, MSc, MD/PhD (University of Massachusetts Medical School); Zachary Kunicki, PhD (Brown University); Douglas Tommet, MPH (Brown University); Shrunjal Trivedi (BIDMC).

Abbreviations: BIDMC, Beth Israel Deaconess Medical Center; BWH, Brigham and Women’s Hospital; BWFH, Brigham and Women’s Faulkner Hospital; HMS, Harvard Medical School; HSL, Hebrew SeniorLife; MGH, Massachusetts General Hospital; PI, principal investigator