Electroencephalography Guidance of Anesthesia (ENGAGES)

• ClinicalTrials.gov Identifier: NCT02241655
• Recruitment Status: Unknown
• First Posted: September 16, 2014
• Results First Posted: June 18, 2019
• Last Update Posted: July 30, 2019
• Sponsor: Washington University School of Medicine
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Michael Avidan, Washington University School of Medicine

Study Description

Brief Summary:

This study aims to determine whether, compared with usual anesthetic care, an electroencephalography-guided anesthesia protocol is effective at preventing postoperative delirium and its downstream effects, and improving postoperative patient reported health-related quality of life.

Condition or disease	Intervention/treatment	Phase
Delirium	Device: a pragmatic EEG-guided anesthetic protocol	Not Applicable

Detailed Description:

Delirium is one of several geriatric syndromes, and is among the most common postoperative complications, affecting up to 70% of surgical patients older than 60. Delirium is an acute change that manifests as inattention and inability to think logically, and is deeply distressing to patients and their families. Based on our surveys of 1,000 surgical patients, over 30% were worried about experiencing delirium. Delirious patients are unable to participate effectively in rehabilitation exercises and are susceptible to other geriatric syndromes, like falls. The occurrence and duration of delirium are associated with longer intensive care unit and hospital stay, persistent cognitive deterioration, hospital readmission and increased mortality rate. Additionally, delirium carries a huge social and economic burden, costing over $60,000 per patient per year. Despite the importance of delirium to patients and to society, no approach has been proven to prevent postoperative delirium. Furthermore postoperative delirium is frequently unrecognized, and surgical patients are not followed systematically after they are discharged from hospital. Without diagnosing delirium or following patients postoperatively, we are limited in our ability to test the effectiveness of any intervention to prevent or treat postoperative delirium and its sequelae. There is mounting evidence that electroencephalography guidance of general anesthesia can decrease postoperative delirium. Specifically, our group has found that a suppressed electroencephalogram pattern, which occurs with deep anesthesia, is associated with increased delirium and death after surgery. The Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) Study will therefore compare the effectiveness of two anesthetic protocols for reduction of postoperative delirium. One protocol will be based on current standard anesthetic practice, and the other protocol will be based on electroencephalography guidance. We also expect to determine the impact of the anesthetic protocols on patient reported outcomes of health-related quality of life. At Washington University, we have successfully implemented an ambitious study that enrolls patients at the preoperative assessment clinic, and tracks their health and wellbeing at 30 days and at 1-year postoperatively. This will enable us to assess the consequences of postoperative delirium and to determine whether anesthetic management can impact patient reported outcomes, such as health-related quality of life. We shall also explore whether a multi-component safety intervention for delirious patients prevents downstream adverse events, like falls. The ENGAGES study - through its structured anesthesia protocols, its thorough approach to delirium assessment, and its ability to track patients' health and wellbeing postoperatively - is poised to make a major contribution to the care of elderly patients who are at risk of postoperative delirium and other adverse outcomes.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) Study
• Actual Study Start Date: January 2015
• Actual Primary Completion Date: May 2018
• Estimated Study Completion Date: October 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: EEG guided protocol; Participants will have a pragmatic EEG-guided anesthetic protocol during their surgery. Practitioners will modify administration of anesthesia in an attempt to limit the occurrence of EEG burst suppression or persistent suppression.	Device: a pragmatic EEG-guided anesthetic protocol; Other Name: Bispectral Index proprietary processed EEG monitor
No Intervention: Control Arm; Participants will have the standard anesthetic protocol.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Delirium [ Time Frame: 5 days ]
   Delirium will be assessed at baseline and then once a day postoperative for up to 5 days. Patients were assessed for delirium using the Confusion Assessment Method for verbal patients or the Confusion Assessment Method for the Intensive Care Unit for non verbal or intubated patients, and patients medical records were reviewed for evidence of delirium by doctors and nurses assessments. Patients were considered to have delirium by any modality at anytime postoperative day one through five.

Secondary Outcome Measures :

1. Postoperative Falls [ Time Frame: Up to 1 year postoperatively ]
   The hypothesis is that the EEG-guided anesthetic protocol and providing a safety intervention will prevent subsequent injurious falls. Falls will be assessed using the Prevention of Falls Network Europe (ProFaNE) questions. At baseline questions will be asked about preoperative falls, and at 30-days and 1-year postoperatively, questions will be asked about postoperative falls.
2. Health Related Quality of Life [ Time Frame: Up to one year postoperatively ]
   The hypothesis is that the EEG-guided anesthetic protocol will improve postoperative quality of life. Patient self-reported Health-related Quality of Life information will be assessed through the Veteran's RAND 12-item Health Survey at baseline and during follow-up (30-day and 1-year).

Other Outcome Measures:

1. Duration of Delirium [ Time Frame: 5 days ]
   Duration will be calculated by the number of positive CAM,CAM-ICU or delirium chart reviews.
2. Agreements Among the FAM-CAM, Researchers' Delirium Assessments and Patient Perceptions [ Time Frame: 5 days ]
   The Family Confusion Assessment Method (FAM-CAM) instrument has previously been shown to have good agreement with the CAM and with DSM-IV diagnostic criteria in patients with cognitive impairment and in hospitalized patients.
3. Duration or Recurrence of Delirium After Hospital Discharge [ Time Frame: 30 days post discharge ]
   As measured by the FAM-CAM and patient perceptions
4. Clinically Relevant Outcomes Associated With Delirium [ Time Frame: 1 year ]
   Delirium incidence, duration and severity have all been shown to be associated with other (downstream) clinically relevant outcomes, including mortality, length of ICU stay, length of hospital stay, falls, cognitive decline and functional decline.
5. Comparison of Patient-reported and Observational Pain Scores [ Time Frame: 5 days ]
   Given that postoperative delirium is common and may relate to uncontrolled pain, this has important implications for the assessment and treatment of postoperative pain. We plan to compare patient reported and behavioral pain assessments in both non-delirious and delirious patients.
6. Postoperative Actigraphy [ Time Frame: 1 day ]
   Postoperative disturbances in sleep abnormalities have previously been associated with postoperative delirium. Measures of root mean-squared activity (RMSactivity) was calculated by combining counts (binned in 1-minute intervals) across all three accelerometer axes (X, Y, and Z) from 16:00 on the day of surgery to 6:00 the following day. Median activity count was calculated from all minutes with nonzero RMS activity within each epoch- higher values indicate more movement.
7. Relationship Between Clinical CAM-ICU and Rigorous Delirium Assessments [ Time Frame: 5 days ]
   Routine clinical (i.e. conducted by ICU nursing staff) delirium assessments in the intensive care units (conducted with the CAM-ICU) will be collected when these are available. Comparison will be made on the outcome of the assessment (positive for delirium or negative by delirium) between these routine clinical assessments and the assessments made by the research team. Since the purpose of this is to determine whether clinical staff are picking up episodes of delirium compared to researcher's assessment in all patients regardless of treatment group, data from both treatment arms were combined for the analysis.
8. Postoperative Outcomes Hypothesized to be Associated With Anesthetic Depth [ Time Frame: 1 year ]
   There is an ongoing randomized, clinical trial investigating the effects of depth of anesthesia on a range of outcomes98, including death, myocardial infarction, cardiac arrest, pulmonary embolus, stroke, surgical site infection, ICU length of stay, hospital length of stay, intraoperative awareness, persistent pain and cancer recurrence. Many of these outcomes are tracked with the SATISFY-SOS study, and will therefore be reported for patients enrolled in the ENGAGES study.
9. Delirium Prediction Models [ Time Frame: 5 days ]
   It is important to improve our understanding of factors that are associated with an increased incidence of postoperative delirium or perhaps may even mediate an elevated risk for postoperative delirium. The arm/group was included in the model to determine if it was associated with postoperative delirium therefore data is not presented by arm/group.
10. Collaborations With Other Studies [ Time Frame: 5 years ]
    The ENGAGES study is being conducted in collaboration with complementary trials at the University of California, San Francisco (UCSF) (NCT01983384), the University of Michigan in Ann Arbor and the University of Manitoba in Winnipeg. Some of the outcomes will be analyzed considering data from some or all of these studies, as appropriate. In terms of the practicality of disseminating the EEG-guided protocol in North America and beyond, it will be important to demonstrate the feasibility and impact of the protocol in multiple sites.
11. Number of Participants With Severe Delirium [ Time Frame: 5 days ]
    The severity of delirium will be scored using the CAM-Severity (CAM-S) metric, which has specifically been shown to be strongly associated with clinically relevant outcomes. Severe delirium was defined as patients with a CAM-S score of 10 or greater (range 0-19).
12. EEG and Delirium [ Time Frame: 5 days ]
    EEG abnormalities have previously been associated with postoperative delirium
13. Postoperative Actigraphy- Immobile Minutes [ Time Frame: 1 day ]
    Postoperative disturbances in sleep abnormalities have previously been associated with postoperative delirium. Measures of root mean-squared activity (RMSactivity) was calculated by combining counts (binned in 1-minute intervals) across all three accelerometer axes (X, Y, and Z) from 16:00 on the day of surgery to 6:00 the following day. We quantified inactivity using the number of immobile minutes, defined as the total number of minutes with an RMSactivity count of zero- higher number indicates patient had more time being immobile.

Eligibility Criteria

• Ages Eligible for Study: 60 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion:

• Patients 60 years old and older,
• Competent to provide informed consent
• Undergoing major elective surgery that requires a minimum stay of 2 days postoperatively (e.g., open cardiac surgery, open thoracic surgery, major vascular surgery, intra-abdominal surgery, open gynecologic surgery, open urologic surgery, major orthopedic surgery, open hepato-biliary surgery and major ear, nose and throat surgery)

Exclusions

• Neurosurgical procedures will be excluded as surgery on the brain can confound the outcome (postoperative delirium).
• Patients with preoperative delirium and patients who are unable to participate adequately in delirium screening including those who are blind, deaf, or illiterate or fluent in languages other than English.

Contacts and Locations

Locations

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

Sponsors and Collaborators

Washington University School of Medicine

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Michael S. Avidan, MBBCh, FCASA; Washington University School of Medicine
• Study Director: Eric Lenze, MD; Washington University School of Medicine
• Study Director: Nan Lin, PhD; Washington University School of Medicine
• Study Director: Susan Stark, PhD; Washington University School of Medicine
• Study Director: Troy Wildes, MD; Washington University School of Medicine
• Study Director: Anke Winter, MD; Washington University School of Medicine
• Study Director: Sharon Inouye, MD; Hebrew Rehabilitation Center
• Study Director: Arbi Ben Abdallah, PhD; Washington University School of Medicine

  Study Documents (Full-Text)

Documents provided by Michael Avidan, Washington University School of Medicine:

Study Protocol and Statistical Analysis Plan: Study protocol with analysis plan  [PDF] December 21, 2015

Statistical Analysis Plan: Updated Analysis plan for 1 year  [PDF] June 21, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Guay CS, Kafashan M, Huels ER, Jiang Y, Beyoglu B, Spencer JW, Geczi K, Apakama G, Ju YS, Wildes TS, Avidan MS, Palanca BJA. Postoperative Delirium Severity and Recovery Correlate With Electroencephalogram Spectral Features. Anesth Analg. 2023 Jan 1;136(1):140-151. doi: 10.1213/ANE.0000000000006075. Epub 2022 May 13.

Fritz BA, King CR, Mickle AM, Wildes TS, Budelier TP, Oberhaus J, Park D, Maybrier HR, Ben Abdallah A, Kronzer A, McKinnon SL, Torres BA, Graetz TJ, Emmert DA, Palanca BJ, Stevens TW, Stark SL, Lenze EJ, Avidan MS; ENGAGES Research Group. Effect of electroencephalogram-guided anaesthesia administration on 1-yr mortality: follow-up of a randomised clinical trial. Br J Anaesth. 2021 Sep;127(3):386-395. doi: 10.1016/j.bja.2021.04.036. Epub 2021 Jul 7.

Wildes TS, Mickle AM, Ben Abdallah A, Maybrier HR, Oberhaus J, Budelier TP, Kronzer A, McKinnon SL, Park D, Torres BA, Graetz TJ, Emmert DA, Palanca BJ, Goswami S, Jordan K, Lin N, Fritz BA, Stevens TW, Jacobsohn E, Schmitt EM, Inouye SK, Stark S, Lenze EJ, Avidan MS; ENGAGES Research Group. Effect of Electroencephalography-Guided Anesthetic Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES Randomized Clinical Trial. JAMA. 2019 Feb 5;321(5):473-483. doi: 10.1001/jama.2018.22005.

Maybrier HR, King CR, Crawford AE, Mickle AM, Emmert DA, Wildes TS, Avidan MS, Palanca BJA; ENGAGES Study Investigators. Early Postoperative Actigraphy Poorly Predicts Hypoactive Delirium. J Clin Sleep Med. 2019 Jan 15;15(1):79-87. doi: 10.5664/jcsm.7576.

Aranake-Chrisinger A, Cheng JZ, Muench MR, Tang R, Mickle A, Maybrier H, Lin N, Wildes T, Lenze E, Avidan MS. Ability of postoperative delirium to predict intermediate-term postoperative cognitive function in patients undergoing elective surgery at an academic medical centre: protocol for a prospective cohort study. BMJ Open. 2018 Mar 17;8(3):e017079. doi: 10.1136/bmjopen-2017-017079.

Mickle AM, Maybrier HR, Winter AC, McKinnon SL, Torres BA, Lin N, Lenze EJ, Stark S, Muench MR, Jacobsohn E, Inouye SK, Avidan MS, Wildes TS; ENGAGES Research Group*. Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial. Anesth Analg. 2018 Jun;126(6):1851-1858. doi: 10.1213/ANE.0000000000002680.

Cui V, Tedeschi CM, Kronzer VL, McKinnon SL, Avidan MS. Protocol for an observational study of delirium in the post-anaesthesia care unit (PACU) as a potential predictor of subsequent postoperative delirium. BMJ Open. 2017 Jul 10;7(7):e016402. doi: 10.1136/bmjopen-2017-016402.

Wildes TS, Winter AC, Maybrier HR, Mickle AM, Lenze EJ, Stark S, Lin N, Inouye SK, Schmitt EM, McKinnon SL, Muench MR, Murphy MR, Upadhyayula RT, Fritz BA, Escallier KE, Apakama GP, Emmert DA, Graetz TJ, Stevens TW, Palanca BJ, Hueneke R, Melby S, Torres B, Leung JM, Jacobsohn E, Avidan MS. Protocol for the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study: a pragmatic, randomised clinical trial. BMJ Open. 2016 Jun 15;6(6):e011505. doi: 10.1136/bmjopen-2016-011505. Erratum In: BMJ Open. 2016 Jun 27;6(6):e011505corr1.

• Responsible Party: Michael Avidan, Professor of Anesthesiology, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT02241655
• Other Study ID Numbers: 201407128; 1UH2AG050312-01 ( U.S. NIH Grant/Contract )
• First Posted: September 16, 2014
• Results First Posted: June 18, 2019
• Last Update Posted: July 30, 2019
• Last Verified: July 2019

Keywords provided by Michael Avidan, Washington University School of Medicine:

Anesthesia; Electroencephalography; Burst suppression; Surgery; Delirium; Falls; Health related quality of life

Additional relevant MeSH terms:

Delirium; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs