Hemodynamic Instability, Neurocognitive Dysfunction, Pain, Postoperative Delirium
Conditions
Brief summary
In the PATHFINDER 2 trial, the study investigators will test the intraoperative EEG-guided multimodal general anesthesia (MMGA) management strategy in combination with a postoperative protocolized analgesic approach to: 1. reduce the incidence of perioperative neurocognitive dysfunction in cardiac surgical patients 2. ensure hemodynamic stability and decrease use of vasopressors in the operating rooms 3. reduce pain and opioid consumption postoperatively
Detailed description
The investigators propose to randomize (1:1) 70 patients undergoing cardiac surgery to the perioperative EEG-guided MMGA bundle (described in full below) or standard-of-care management based primarily on the use of sevoflurane for unconsciousness and intermittent doses of fentanyl and hydromorphone for antinociception. The team will test the intraoperative EEG-guided MMGA management strategy in combination with a postoperative protocolized analgesic approach to reduce the postoperative increase of surgical and delirium markers, reduce intraoperative abnormalities in brain health monitoring, ensure hemodynamic stability and decreased use of vasopressors in the operating rooms and reduce pain and opioid consumption postoperatively. The team will also investigate whether EEG-guided MMGA strategy reduces the incidence of perioperative neurocognitive dysfunction in cardiac surgical patients. This approach will further individualize care and minimize the use of intraoperative vasopressor-inotropic dose, dose of anesthetic medications, and postoperative opioids given to each patient potentially preventing hemodynamic complications and post-operative cognitive dysfunction after surgery.
Interventions
DEVICEEEG Monitoring
Perioperative monitoring, MMGA guided by EEG for intervention group
DRUGRopivacaine
Intraoperative bilateral PIFB block with 20 mL of 0.2% Ropivicaine on either side of the sternum after anesthetic induction but before surgical incision (total of 40mL) PIFB on postoperative day 1 (provided they are extubated or getting ready to be extubated) to help with mobilization (for intervention group)
DRUGKetamine
Intraoperative infusion
DRUGRemifentanil
Intraoperative infusion
DRUGDexmedetomidine
Intraoperative infusion
DRUGRocuronium
Intraoperative intermittent bolus
DRUGPropofol
Intraoperative infusion
Sponsors
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Intervention model description
Group 1: Control - receives standard of care anesthesia and blinded EEG and Cerebral Oximetry(CO) monitoring Group 2: Intervention - receives MMGA bundle, guided by EEG monitoring, blinded CO will be passively collected
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 60 years * Undergoing any of the following types of surgery with cardiopulmonary bypass limited to coronary artery bypass surgery (CABG), CABG+valve surgeries and isolated valve surgeries.
Exclusion criteria
* Preoperative left ventricular ejection fraction (LVEF) \<30% * Emergent surgery * Non-English speaking * Cognitive impairment as defined by total MoCA score \< 10 * Currently enrolled in another interventional study that could impact the primary outcome, as determined by the PI * Significant visual impairment * Chronic opioid use for chronic pain conditions with tolerance (total dose of an opioid at or more than 30 mg morphine equivalent for more than one month within the past year) * Hypersensitivity to any of the study medications * Known history of alcohol (\> 2 drinks per day) or drug abuse Active (in the past year) history of alcohol abuse (≥5 drinks/day for men or ≥4 drinks/day for women) as determined by reviewing medical record and history given by the patient * Liver dysfunction (liver enzymes \> 4 times the baseline, all patients will have a baseline liver function test evaluation), history and examination suggestive of jaundice.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Increase in Plasma IL-6 Levels | Baseline, postoperative day 1, and postoperative day 2 | Plasma interleukin-6 (IL-6) levels will be measured at baseline, postoperative day 1, and postoperative day 2. The change in IL-6 concentration from baseline to each postoperative time point will be calculated and compared between the study groups. |
| Increase in Plasma Neurofilament Light Levels | Baseline, postoperative day 1, and postoperative day 2 | Plasma neurofilament light (NfL) levels will be measured at baseline, postoperative day 1, and postoperative day 2. The change in NfL concentration from baseline to each postoperative time point will be calculated and compared between the study groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Burst Suppression | intraoperative period, from anesthetic induction until the end of surgery | Duration of burst suppression was extracted and quantified from the intraoperative EEG record and compared between the MMGA and control groups. |
| Postoperative Delirium | From postoperative day 1 until hospital discharge, an average of 4 days | Incidence of Postoperative Delirium (POD) will be compared between both groups: POD will be diagnosed by our trained research members based on the Confusion Assessment Method (CAM) algorithm postoperatively until discharge. |
| Opioid Consumption | From end of surgery to 48 hours postoperatively | Total opioid consumption during the first 48 postoperative hours will be calculated by summing all opioid doses administered in any route and converting to intravenous morphine milligram equivalents (MME) for standardization. The cumulative 48-hour opioid dose will be compared between groups. |
| Hemodynamic Stability - Total Vasopressor Dose | Intraoperative period, from induction of anesthesia until transfer from the operating room | Metrics of total vasopressor dose in norepinephrine equivalents (mcg/kg/min) will be collected from the intra-operative record and medical records to be quantified and compared. |
| Cognitive Function | Patients will be assessed for cognitive function at 1 month and 6 months following the date of surgery | Postoperative cognitive function will be assessed at 1 and 6 months after surgery using the telephone version of the Montreal Cognitive Assessment (t-MoCA). The t-MoCA has a total score range of 0 to 22, where higher scores indicate better cognitive function. |
| Pain Scores | From end of surgery to 48 hours postoperatively | Postoperative pain intensity will be assessed using the Numeric Rating Scale (NRS), a validated 11-point scale that measures patient-reported pain intensity from 0 to 10, where 0 indicates no pain and 10 indicates the worst possible pain. Scores will be obtained by nursing staff every 4-8 hours from electronic medical records, and the average 48-hour postoperative pain score will be compared between groups. |
Countries
United States
Participant flow
Recruitment details
Participants undergoing elective cardiac surgery were recruited from a tertiary academic hospital between February 28, 2023, and December 31, 2024, for a randomized trial comparing EEG-guided multimodal general anesthesia with standard care. Recruitment occurred in preoperative clinics, inpatient wards, and surgical units.
Pre-assignment details
There were no washout, run-in, or lead-in phases. All enrolled participants were randomized in a 1:1 ratio to either the EEG-guided multimodal general anesthesia (MMGA) group or the standard care group without pre-assignment exclusions.
Participants by arm
| Arm | Count |
|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided 1. Routine anesthetic induction
2. Bilateral Pectoro-interfascial block (PIFB) with 20 mL of 0.2% ropivacaine on both sides of the sternum after anesthetic induction but before surgical incision (total of 40mL)
3. Ketamine (0.1 to 0.2 mg.kg/hr)
4. Remifentanil (0.05-0.4 mcg/kg/min)
5. Dexmedetomidine (0.2-0.5 mcg/kg/hr)
6. Rocuronium intermittent bolus (TOF)
7. Propofol infusion (15 to 200 mcg/kg/min)
Postop
1. Standard pain management protocol
* IV Acetaminophen
* IV Hydromorphone/fentanyl boluses as needed per current practice for rescue analgesia
* Other oral pain medications as per standard of care (Oxycodone, etc)
2. Dexmedetomidine infusion (0.4-1.4 mcg/kg/hr) - EEG Guided; Infusion continued till extubation
3. Propofol infusion may be added/used for sedation based on the treating physician's discretion
4. PIFB on postoperative day 1 (provided they are extubated/getting ready to be extubated)(for intervention group)
5. Lidocaine patches | 34 |
| Standard of Care/Control EEG monitoring will be blinded, and not guide anesthesiologists. Patients will receive standard/routine anesthesia practice intraoperatively.
Postoperative Propofol infusion (15 to 200 mcg/kg/min) ± Sevoflurane
1. Standard pain management protocol
* IV Acetaminophen (1 gram) x 4 doses at 6 hour intervals starting from 1 hr after ICU arrival
* IV Hydromorphone/fentanyl boluses as needed per current practice for rescue analgesia
* Other oral pain medications as per standard of care (Oxycodone, etc)
2. Dexmedetomidine infusion (0.4-1.4 mcg/kg/hr) - EEG Guided; Infusion continued till extubation
3. Propofol infusion may be added/used for sedation based on the treating physician's discretion
4. Lidocaine patches
5. Parasternal block (PIFB or Transversus Thoracic Plane Block) on Postoperative day 0 - currently incorporated into standard pain management after surgery based on physician discretion | 35 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Standard of Care/Control | Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Total |
|---|---|---|---|
| Age, Continuous | 71 years STANDARD_DEVIATION 7 | 70 years STANDARD_DEVIATION 6 | 70.507 years STANDARD_DEVIATION 6.5 |
| Baseline plasma IL-6 and NFL Levels IL-6 - Baseline | 29.5 pg/mL STANDARD_DEVIATION 79.9 | 15 pg/mL STANDARD_DEVIATION 28.5 | 22.03 pg/mL STANDARD_DEVIATION 59.15 |
| Baseline plasma IL-6 and NFL Levels NFL Baseline | 28.6 pg/mL STANDARD_DEVIATION 37.4 | 40.9 pg/mL STANDARD_DEVIATION 37.1 | 34.93 pg/mL STANDARD_DEVIATION 37.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 33 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 33 Participants | 30 Participants | 63 Participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 27 Participants | 29 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 34 |
| other Total, other adverse events | 0 / 33 | 0 / 34 |
| serious Total, serious adverse events | 0 / 33 | 0 / 34 |
Outcome results
Primary
Increase in Plasma IL-6 Levels
Plasma interleukin-6 (IL-6) levels will be measured at baseline, postoperative day 1, and postoperative day 2. The change in IL-6 concentration from baseline to each postoperative time point will be calculated and compared between the study groups.
Time frame: Baseline, postoperative day 1, and postoperative day 2
Population: The number of participants analyzed at each time point differs from the number originally assigned due to missing or inadequate biospecimen samples for IL-6 and NFL measurements at baseline and postoperative days 1 and 2. Participants without valid samples at a given time point were excluded from that specific analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Increase in Plasma IL-6 Levels | IL-6 - Baseline | 15 pg/mL | Standard Deviation 28.5 |
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Increase in Plasma IL-6 Levels | Il-6 - POD1 | 80.5 pg/mL | Standard Deviation 65.4 |
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Increase in Plasma IL-6 Levels | IL-6 - POD2 | 115.7 pg/mL | Standard Deviation 64.1 |
| Standard of Care/Control | Increase in Plasma IL-6 Levels | IL-6 - Baseline | 29.5 pg/mL | Standard Deviation 79.9 |
| Standard of Care/Control | Increase in Plasma IL-6 Levels | Il-6 - POD1 | 97.7 pg/mL | Standard Deviation 93.5 |
| Standard of Care/Control | Increase in Plasma IL-6 Levels | IL-6 - POD2 | 164 pg/mL | Standard Deviation 108.7 |
Primary
Increase in Plasma Neurofilament Light Levels
Plasma neurofilament light (NfL) levels will be measured at baseline, postoperative day 1, and postoperative day 2. The change in NfL concentration from baseline to each postoperative time point will be calculated and compared between the study groups.
Time frame: Baseline, postoperative day 1, and postoperative day 2
Population: The number of participants analyzed at each time point differs from the number originally assigned due to missing or inadequate biospecimen samples for IL-6 and NFL measurements at baseline and postoperative days 1 and 2. Participants without valid samples at a given time point were excluded from that specific analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Increase in Plasma Neurofilament Light Levels | NFL - Baseline | 40.9 pg/mL | Standard Deviation 37.1 |
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Increase in Plasma Neurofilament Light Levels | NFL - POD1 | 37.4 pg/mL | Standard Deviation 39.5 |
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Increase in Plasma Neurofilament Light Levels | NFL - POD2 | 56.8 pg/mL | Standard Deviation 49.3 |
| Standard of Care/Control | Increase in Plasma Neurofilament Light Levels | NFL - Baseline | 28.6 pg/mL | Standard Deviation 37.4 |
| Standard of Care/Control | Increase in Plasma Neurofilament Light Levels | NFL - POD1 | 25.8 pg/mL | Standard Deviation 23.2 |
| Standard of Care/Control | Increase in Plasma Neurofilament Light Levels | NFL - POD2 | 52.8 pg/mL | Standard Deviation 46.5 |
Secondary
Burst Suppression
Duration of burst suppression was extracted and quantified from the intraoperative EEG record and compared between the MMGA and control groups.
Time frame: intraoperative period, from anesthetic induction until the end of surgery
Population: 5 subjects from the intervention group and 4 subjects in control group are removed from analysis due to artifacts in EEG data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Burst Suppression | 4.83 minutes | Standard Deviation 3.47 |
| Standard of Care/Control | Burst Suppression | 1.68 minutes | Standard Deviation 2.2 |
Secondary
Cognitive Function
Postoperative cognitive function will be assessed at 1 and 6 months after surgery using the telephone version of the Montreal Cognitive Assessment (t-MoCA). The t-MoCA has a total score range of 0 to 22, where higher scores indicate better cognitive function.
Time frame: Patients will be assessed for cognitive function at 1 month and 6 months following the date of surgery
Population: Lost to follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Cognitive Function | 1 month follow-up | 18.421 scores on a scale | Standard Deviation 2.631 |
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Cognitive Function | 6 month follow-up | 18.100 scores on a scale | Standard Deviation 2.075 |
| Standard of Care/Control | Cognitive Function | 1 month follow-up | 18.174 scores on a scale | Standard Deviation 2.855 |
| Standard of Care/Control | Cognitive Function | 6 month follow-up | 18.960 scores on a scale | Standard Deviation 1.767 |
Secondary
Hemodynamic Stability - Total Vasopressor Dose
Metrics of total vasopressor dose in norepinephrine equivalents (mcg/kg/min) will be collected from the intra-operative record and medical records to be quantified and compared.
Time frame: Intraoperative period, from induction of anesthesia until transfer from the operating room
Population: 3 subjects change of consent status before surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Hemodynamic Stability - Total Vasopressor Dose | 1109.425 norepinephrine equivalents (mcg/kg/min) | Standard Deviation 2311.095 |
| Standard of Care/Control | Hemodynamic Stability - Total Vasopressor Dose | 2358.042 norepinephrine equivalents (mcg/kg/min) | Standard Deviation 4543.262 |
Secondary
Opioid Consumption
Total opioid consumption during the first 48 postoperative hours will be calculated by summing all opioid doses administered in any route and converting to intravenous morphine milligram equivalents (MME) for standardization. The cumulative 48-hour opioid dose will be compared between groups.
Time frame: From end of surgery to 48 hours postoperatively
Population: 2 subjects in intervention group and 1 subject in control group withdrew from study after the consent before the start of study procedure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Opioid Consumption | 132.42 Morphine Milligram Equivalents (MME) | Standard Deviation 77.05 |
| Standard of Care/Control | Opioid Consumption | 126.93 Morphine Milligram Equivalents (MME) | Standard Deviation 58.12 |
Secondary
Pain Scores
Postoperative pain intensity will be assessed using the Numeric Rating Scale (NRS), a validated 11-point scale that measures patient-reported pain intensity from 0 to 10, where 0 indicates no pain and 10 indicates the worst possible pain. Scores will be obtained by nursing staff every 4-8 hours from electronic medical records, and the average 48-hour postoperative pain score will be compared between groups.
Time frame: From end of surgery to 48 hours postoperatively
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Pain Scores | 4.33 Scores on a scale | Standard Deviation 1.56 |
| Standard of Care/Control | Pain Scores | 4.72 Scores on a scale | Standard Deviation 1.69 |
Secondary
Postoperative Delirium
Incidence of Postoperative Delirium (POD) will be compared between both groups: POD will be diagnosed by our trained research members based on the Confusion Assessment Method (CAM) algorithm postoperatively until discharge.
Time frame: From postoperative day 1 until hospital discharge, an average of 4 days
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Multimodal General Anesthesia (MMGA Bundle) - EEG Guided | Postoperative Delirium | 8 Participants with delirium | 2.6 |
| Standard of Care/Control | Postoperative Delirium | 9 Participants with delirium | 2.78 |