Prediction and Prevention of Postoperative Mortality and Morbidity

Alzheimer Disease Clinical Trial

Official title:

Real-world and Innovative Multimodal Prediction and Prevention of Postoperative Mortality and Multi-morbidities

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06042413
• Other study ID #: STUDY22070046
• Secondary ID: 1R01AG081315
• Status: Not yet recruiting
• Phase: N/A
• Start date: July 1, 2024
• Est. completion date: September 1, 2025

Study information

• Verified date: April 2024
• Source: University of Pittsburgh
• Contact: Alisha Maslanka, BS, CCRC
• Phone: 4128646779
• Email: maslankaaa[@]upmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will contribute to creating a prospective and robust automated preoperative risk assessment algorithm for 30-day mortality, major adverse cardiac and cerebrovascular events (MACCE) and perioperative neurocognitive disorders (PND) outcomes following elective general, orthopedic, cardiac, or vascular surgery. It will help to identify correlations between perioperative factors and Alzheimer's Disease (AD) or AD-related dementias (ADRD). Lastly, this study will create effective, validated multi-modal interventions to improve perioperative health. This study will explore two main hypotheses: 1. Preoperative prehabilitation and proactive cognitive/behavioral interventions will effectively improve postoperative cognitive outcomes, morbidities, and mortality, and; 2. The proactive bundled interventions are superior to current standard of care in reducing postoperative cognitive outcomes, MACCE and mortality. Expected Outcome: Improved EHR algorithm will have higher predictive accuracy for MACCE and mortality while predicting postoperative cognitive outcomes.

Description:

This study will cover the following two specific aims:

Aim 1. A randomized controlled trial (RCT) to assess the effectiveness of pre-operative personalized prehabilitation with proactive cognitive and behavioral interventions versus standard of care on reducing postoperative cognitive outcomes (POD, POCD, dementia), MACCE, and mortality in high-risk surgical elderly patients (≥65y). Our Electronic Health Record (EHR)-based automated machine-learning risk prediction algorithm for postoperative mortality and MACCE has been developed using >1.25 million surgical patients' data and implemented with superior performance to comparators. This EHR algorithm will identify 1000 patients at high risk for 30-day mortality and MACCE for Aim 1. Patients will be stratified by baseline cognition status and randomly assigned to standard of care (n=500) or personalized preoperative prehabilitation with proactive cognitive/behavioral interventions (physical exercise, cognitive training, enhanced social support, and proactive depression treatment) (n=500). Cognitive assessments will be performed at baseline, at discharge, 1-, 3-, 6-, and 12- months.

Aim 1 Hypothesis: Preoperative prehabilitation and proactive cognitive/behavioral interventions will effectively improve postoperative cognitive outcomes, morbidities, and mortality.

Aim 2: An RCT to examine the effectiveness of proactive intra-operative bundled interventions versus reactive standard of care to improve postoperative cognitive outcomes, MACCE, and mortality in high-risk surgical elderly patients scheduled for cardiac surgery with IONM. Intraoperative factors are associated with mortality, morbidity, and stroke. Intraoperative triple-low events (mean arterial pressure <75 mmHg, Bispectral Index <45, and minimum alveolar fraction <0.8) are associated with postoperative cognitive outcomes. Eligible patients scheduled for IONM from Aim 1 (n=500) will be stratified based on Aim 1 intervention groups and randomized to either reactive standard of care intervention (n=250) or proactive bundled interventions to determine if optimizing intraoperative physiology reduces postoperative cognitive outcomes and 30-day MACCE and mortality. Both groups will receive reactive response to shifts in electroencephalography (EEG) and somatosensory evoked potential (SSEP). Proactive bundled interventions91 include maintaining normal blood pressure, oxygen levels, opioid sparing analgesia92-94, avoiding deep anesthesia95 and benzodiazepines.

Aim 2 Hypothesis: The proactive bundled interventions are superior to current standard of care in reducing postoperative cognitive outcomes, MACCE and mortality. Expected Outcome: Improved EHR algorithm will have higher predictive accuracy for MACCE and mortality while predicting postoperative cognitive outcomes

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1200
• Est. completion date: September 1, 2025
• Est. primary completion date: September 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Part I Inclusion Criteria:

• 65 years of age and older

• Identified as higher risk (=2.5%) for 30-day mortality and MACCE based on the UPMC's Perioperative Model (EHR risk prediction algorithm)

• Scheduled for major cardiac surgeries including coronary artery bypass and valvular repair and/or vascular surgeries including carotid endarterectomy, aortic aneurysm repair, and major vascular surgeries

• RAI score = 30

• PHQ-9 score = 5

• Anticipated length of stay > 3 days

• Informed consent

• English speaking patients

• All races and ethnicities

• Diverse background (education, area deprivation index)

Part II Inclusion Criteria:

• Patients undergoing high-risk cardiac and vascular surgery, such as intraoperative bypass for cardiac surgeries and carotid endarterectomy/ aortic aneurysm vascular surgeries.

• History of fully resolved stroke and TIA without any residual weakness

• Significant carotid artery stenosis (defined as >70% unilateral or bilateral stenosis)

• Moderate and high risk for mortality based on Society of Thoracic Surgery score (score >4)

• Enrolled in Part 1, "Randomized controlled clinical trial to assess the effectiveness of preoperative personalized prehabilitation as well as cognitive and behavioral interventions on reducing postoperative delirium (POD), postoperative cognitive dysfunction (POCD), dementia, 30-day major adverse cardiac and cerebrovascular events (MACCE) and mortality in high-risk surgical patients (=65y)."

Part I Exclusion Criteria:

• Children (<18 years)

• Patients unable to provide consent

• MoCA score <23

• Persistent weakness from prior cerebrovascular accident

• Patients with severe preoperative medical diseases, blindness or significant visual impairment, unresolved motor weakness, or any other perioperative events or complications that would have a bearing on the patients' ability to perform study tasks, neuropsychological tests and proposed interventions

Part II Exclusion Criteria:

• Pregnant women

• Patients do not provide consent.

• Patients are unable to participate in cognitive and other behavioral assessment due to physical limitations

• Patients refuse any blood transfusions during surgery

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Other:
• Personalized CPC Prehabilitation
Patients for elective surgery randomized to the intervention group will be scheduled for a preoperative evaluation (3-6 weeks prior to the surgical date) and will receive standardized and personalized assessment and prehabilitation according to UPMC's established disease-specific algorithms.

Behavioral:
• Cognitive Training
Participants will be provided with access to the Lumosity (Lumos Labs) software for installation on a home device. They will be trained to navigate the touchscreen tablet and guided through an introductory series of brain exercise games focused on 5 main categories: memory, speed, attention, flexibility, and problem-solving. Patients will be asked to complete a cognitive exercise dosage of a minimum of 20 minutes a day for =5 days prior to their date of surgery. Research coordinators and volunteers from UPMC's Hospital Elder Life Program (HELP) will reach out to participants daily for a quick social check-in and to remind them to perform their training. Compliance data will be retrieved from the Lumosity app.
• Meditation
A single guided meditation session with instructions will be provided using a smart device. The meditation session will last for at least 10 minutes daily starting at least 1-week prior to surgery. If the subject does not own a smart device, one will be provided or meditation will be completed in-person or over the phone.
• Daily Exercise
Participants in the intervention group will meet with an occupational or physical therapist approximately 1-6 weeks before surgery who will discuss the potential benefits of exercise and give directions for an easy strength training exercise. Participants will then be provided with a video link for a guided exercise and encouraged to walk or perform a seated strength exercise for = 5 minutes each day for at least 1 week before surgery and after surgery. Patient reported frequency, fitness app compliance and exercise duration with REDCap email or mobile link or over telephone will be collected before and after surgery. Patients will be cleared by an occupational or physical therapist to perform the upper-extremity exercises and will confirm the exercises are not contraindicated after surgery. An occupational or physical therapist will see subject again post-surgery to mitigate risk of injury.
• Enhanced Social Support
Research coordinators and volunteers from HELP will reach out to patients daily prior to their surgery to discuss concerns they may have, provide daily social touchpoints, and remind them to perform their cognitive exercises. In addition, the importance of social support will be discussed with family members and other caregivers and they will be encouraged to participate. e. Proactive depression treatment: All patients will receive preoperative interventions to manage their depression under their CPC prehabilitation program.

Other:
• Proactive Bundle Interventions
Participants randomized to the proactive bundled intervention group (Group D) will receive a routine intraoperative SSEP and EEG monitoring as well as optimization of intraoperative physiology by maintaining normal blood pressure, oxygen levels, opioid sparing analgesia, avoiding deep anesthesia and benzodiazepines. For example, increasing mean arterial pressure can stabilize SSEP (Fig. 6). If persistent focal changes in SSEP and EEG, (i.e., changes in one hemisphere) occur efforts will be made to increase brain perfusion by ensuring and maintaining hematocrit >30, MAP >70, and anesthetic BIS >50-60; soon after surgery, patients will get stroke management and thrombectomy if indicated.

Procedure:
• Pre-operative Standard of Care
Patients in the control group will receive standard of care pre-operative treatment, which may or may not include a visit to the CPC.
• Intra-operative Standard of Care
This includes routine intraoperative SSEP and EEG monitoring. Physician oversight and interpretation of real-time neuromonitoring data will be performed using a combined on-site and remote model at UPMC. In the event that changes in EEG or SSEP are considered significant by the oversight neurophysiologists, the surgical team will be immediately informed so that immediate appropriate action can be taken to reverse the change.

Locations

Country	Name	City	State
United States	UPMC Presbyterian Hospital	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pittsburgh	National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cognitive Outcomes - Dementia	Clinical Dementia Rating Instrument (CDR) will be used to assess dementia. Ratings are as follows: 0 = none, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe	Preoperative baseline screening
Primary	Cognitive Outcomes - Dementia	Clinical Dementia Rating Instrument (CDR) will be used to assess dementia. Ratings are as follows: 0 = none, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe	At time of hospital discharge (up to day 5)
Primary	Cognitive Outcomes - Dementia	Clinical Dementia Rating Instrument (CDR) will be used to assess dementia. Ratings are as follows: 0 = none, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe	Postoperative 1-month
Primary	Cognitive Outcomes - Dementia	Clinical Dementia Rating Instrument (CDR) will be used to assess dementia. Ratings are as follows: 0 = none, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe	Postoperative 3-months
Primary	Cognitive Outcomes - Dementia	Clinical Dementia Rating Instrument (CDR) will be used to assess dementia. Ratings are as follows: 0 = none, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe	Postoperative 6-months
Primary	Cognitive Outcomes - Dementia	Clinical Dementia Rating Instrument (CDR) will be used to assess dementia. Ratings are as follows: 0 = none, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe	Postoperative 12-months
Primary	Cognitive Outcomes - Delirium	The long CAM-Severity will be used to assess delirium. For a diagnosis of delirium by CAM, the subject must display: 1. Presence of acute onset and fluctuating discourse AND 2. Inattention AND EITHER 3. Disorganized thinking OR 4. Altered level of consciousness. Subjects will be reported as yes/no for delirium.	Preoperative baseline screening
Primary	Cognitive Outcomes - Delirium	The long CAM-Severity will be used to assess delirium. For a diagnosis of delirium by CAM, the subject must display: 1. Presence of acute onset and fluctuating discourse AND 2. Inattention AND EITHER 3. Disorganized thinking OR 4. Altered level of consciousness. Subjects will be reported as yes/no for delirium.	At time of hospital discharge (up to day 5)
Primary	Cognitive Outcomes - Delirium	The long CAM-Severity will be used to assess delirium. For a diagnosis of delirium by CAM, the subject must display: 1. Presence of acute onset and fluctuating discourse AND 2. Inattention AND EITHER 3. Disorganized thinking OR 4. Altered level of consciousness. Subjects will be reported as yes/no for delirium.	Postoperative 1-month
Primary	Cognitive Outcomes - Delirium	The long CAM-Severity will be used to assess delirium. For a diagnosis of delirium by CAM, the subject must display: 1. Presence of acute onset and fluctuating discourse AND 2. Inattention AND EITHER 3. Disorganized thinking OR 4. Altered level of consciousness. Subjects will be reported as yes/no for delirium.	Postoperative 3-months
Primary	Cognitive Outcomes - Delirium	The long CAM-Severity will be used to assess delirium. For a diagnosis of delirium by CAM, the subject must display: 1. Presence of acute onset and fluctuating discourse AND 2. Inattention AND EITHER 3. Disorganized thinking OR 4. Altered level of consciousness. Subjects will be reported as yes/no for delirium.	Postoperative 6-months
Primary	Cognitive Outcomes - Delirium	The long CAM-Severity will be used to assess delirium. For a diagnosis of delirium by CAM, the subject must display: 1. Presence of acute onset and fluctuating discourse AND 2. Inattention AND EITHER 3. Disorganized thinking OR 4. Altered level of consciousness. Subjects will be reported as yes/no for delirium.	Postoperative 12-months
Primary	Cognitive Outcomes - Cognitive Function	The Montreal Cognitive Assessment (MoCA) will be used to assess cognitive functioning. A normal score is considered >/= 26 out of 30 total points.	Preoperative baseline screening
Primary	Cognitive Outcomes - Cognitive Function	The Montreal Cognitive Assessment (MoCA) will be used to assess cognitive functioning. A normal score is considered >/= 26 out of 30 total points.	At time of hospital discharge (up to day 5)
Primary	Cognitive Outcomes - Cognitive Function	The Montreal Cognitive Assessment (MoCA) will be used to assess cognitive functioning. A normal score is considered >/= 26 out of 30 total points.	Postoperative 1-month
Primary	Cognitive Outcomes - Cognitive Function	The Montreal Cognitive Assessment (MoCA) will be used to assess cognitive functioning. A normal score is considered >/= 26 out of 30 total points.	Postoperative 3-months
Primary	Cognitive Outcomes - Cognitive Function	The Montreal Cognitive Assessment (MoCA) will be used to assess cognitive functioning. A normal score is considered >/= 26 out of 30 total points.	Postoperative 6-months
Primary	Cognitive Outcomes - Cognitive Function	The Montreal Cognitive Assessment (MoCA) will be used to assess cognitive functioning. A normal score is considered >/= 26 out of 30 total points.	Postoperative 12-months
Secondary	Cognitive Outcomes - Depression	Patient Health Questionnaire (PHQ-9) will be used to assess depression. Scoring is as follows: 1-4 = minimal depression, 5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe depression, and 20-27 = severe depression	Preoperative baseline screening
Secondary	Cognitive Outcomes - Depression	Patient Health Questionnaire (PHQ-9) will be used to assess depression. Scoring is as follows: 1-4 = minimal depression, 5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe depression, and 20-27 = severe depression	At time of hospital discharge (up to day 5)
Secondary	Cognitive Outcomes - Depression	Patient Health Questionnaire (PHQ-9) will be used to assess depression. Scoring is as follows: 1-4 = minimal depression, 5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe depression, and 20-27 = severe depression	Postoperative 1-month
Secondary	Cognitive Outcomes - Depression	Patient Health Questionnaire (PHQ-9) will be used to assess depression. Scoring is as follows: 1-4 = minimal depression, 5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe depression, and 20-27 = severe depression	Postoperative 3-months
Secondary	Cognitive Outcomes - Depression	Patient Health Questionnaire (PHQ-9) will be used to assess depression. Scoring is as follows: 1-4 = minimal depression, 5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe depression, and 20-27 = severe depression	Postoperative 6-months
Secondary	Cognitive Outcomes - Depression	Patient Health Questionnaire (PHQ-9) will be used to assess depression. Scoring is as follows: 1-4 = minimal depression, 5-9 = mild depression, 10-14 = moderate depression, 15-19 = moderately severe depression, and 20-27 = severe depression	Postoperative 12-months