Prediction and Prevention of Postoperative Mortality and Morbidity

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Alzheimer Disease, Alzheimer Disease Related Dementias

Intervention / Treatment
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* Other: Personalized CPC Prehabilitation
* Behavioral: Cognitive Training
* Behavioral: Meditation
* Behavioral: Daily Exercise
* Behavioral: Enhanced Social Support
* Other: Proactive Bundle Interventions
* Procedure: Pre-operative Standard of Care
* Procedure: Intra-operative Standard of Care


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A total of 1000 participants who are identified as higher risk (≥2.5%) for 30-day mortality and MACCE based on the risk prediction algorithm will be screened and randomized (1:1) to the intervention group (Group A, n=500). The control group (Group B) will receive standard of care (n=500). Based on the preoperative MoCA score, patients will be stratified into normal baseline cognition (MoCA score >= 26) or baseline cognitive dysfunction (MoCA score of 23-25, inclusive) for randomization to balance the baseline cognitive function between the standard of care group and intervention group. All patients scheduled for IONM from Aim 1 will be screened for Aim 2. Eligible participants (estimated  50%, n=500) will be stratified according to their Aim 1 intervention groups and prospectively randomized to either standard of care intraoperative intervention (n=250) (Group C) or proactive bundled interventions (Group D, n=250).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A/C (intervention)<br>Participants randomized to this intervention group will receive the following interventions: Personalized CPC Prehabilitation Cognitive Training Meditation Daily Exercise Enhanced Social Support Additionally, they will undergo standard of care routine intraoperative SSEP and EEG monitoring during the scheduled surgery. | Other: Personalized CPC Prehabilitation<br>* 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.<br>Behavioral: Cognitive Training<br>* 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.<br>Behavioral: Meditation<br>* 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.<br>Behavioral: Daily Exercise<br>* 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.<br>Behavioral: Enhanced Social Support<br>* 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.<br>Procedure: Pre-operative Standard of Care<br>* Patients in the control group will receive standard of care pre-operative treatment, which may or may not include a visit to the CPC.<br>Procedure: Intra-operative Standard of Care<br>* 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.<br>|
| Active Comparator: Group B/C (SOC control)<br>Participants randomized to the control group will receive standard of care pre-operative treatment, which may or may not include a visit to the CPC. Participants will receive standard of care routine intraoperative SSEP and EEG monitoring during the scheduled surgery. | Procedure: Pre-operative Standard of Care<br>* Patients in the control group will receive standard of care pre-operative treatment, which may or may not include a visit to the CPC.<br>Procedure: Intra-operative Standard of Care<br>* 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.<br>|
| Experimental: Group A/D (intervention + SOC)<br>Participants randomized to this intervention group will receive the following interventions for study Part I: Personalized CPC Prehabilitation Cognitive Training Meditation Daily Exercise Enhanced Social Support If eligible to continue to Study Part 2, participants who received the Part I intervention will receive standard of care monitoring that includes: Routine intraoperative SSEP and EEG monitoring. | Other: Personalized CPC Prehabilitation<br>* 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.<br>Behavioral: Cognitive Training<br>* 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.<br>Behavioral: Meditation<br>* 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.<br>Behavioral: Daily Exercise<br>* 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.<br>Behavioral: Enhanced Social Support<br>* 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.<br>Other: Proactive Bundle Interventions<br>* 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.<br>Procedure: Pre-operative Standard of Care<br>* Patients in the control group will receive standard of care pre-operative treatment, which may or may not include a visit to the CPC.<br>Procedure: Intra-operative Standard of Care<br>* 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.<br>|
| Experimental: Group B/D (SOC + proactive bundle interventions)<br>Participants randomized to the control group in study Part I will receive standard of care pre-operative treatment, which may or may not include a visit to the CPC. If eligible to continue to Study Part 2, participants who received standard of care pre-operatively, will receive Proactive Bundle Interventions during surgery that includes: 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. | Other: Proactive Bundle Interventions<br>* 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.<br>Procedure: Pre-operative Standard of Care<br>* Patients in the control group will receive standard of care pre-operative treatment, which may or may not include a visit to the CPC.<br>Procedure: Intra-operative Standard of Care<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 |