Perioperative Multimodal General AnesTHesia Focusing on Specific CNS Targets in Patients Undergoing carDiac surgERies

Study Overview
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Brief Summary
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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: reduce the incidence of perioperative neurocognitive dysfunction in cardiac surgical patients ensure hemodynamic stability and decrease use of vasopressors in the operating rooms reduce pain and opioid consumption postoperatively

Detailed Description
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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.

Official Title
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Perioperative Multimodal General AnesTHesia Focusing on Specific CNS Targets in Patients Undergoing carDiac surgERies - the PATHFINDER II Study

Conditions
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Postoperative Delirium, Hemodynamic Instability, Pain, Neurocognitive Dysfunction

Intervention / Treatment
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* Device: EEG Monitoring
* Drug: Ropivacaine
* Drug: Ketamine
* Drug: Remifentanil
* Drug: Dexmedetomidine
* Drug: Rocuronium
* Drug: Propofol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 60 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: 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multimodal General Anesthesia (MMGA Bundle) - EEG Guided<br>Routine anesthetic induction 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) Ketamine (0.1 to 0.2 mg.kg/hr) Remifentanil (0.05-0.4 mcg/kg/min) Dexmedetomidine (0.2-0.5 mcg/kg/hr) Rocuronium intermittent bolus (TOF) Propofol infusion (15 to 200 mcg/kg/min) Postop 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) Dexmedetomidine infusion (0.4-1.4 mcg/kg/hr) - EEG Guided; Infusion continued till extubation Propofol infusion may be added/used for sedation based on the treating physician's discretion PIFB on postoperative day 1 (provided they are extubated/getting ready to be extubated)(for intervention group) Lidocaine patches | Device: EEG Monitoring<br>* Perioperative monitoring, MMGA guided by EEG for intervention group<br>* Other names: Sedline Monitoring;Drug: Ropivacaine<br>* 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)<br>Drug: Ketamine<br>* Intraoperative infusion<br>Drug: Remifentanil<br>* Intraoperative infusion<br>Drug: Dexmedetomidine<br>* Intraoperative infusion<br>Drug: Rocuronium<br>* Intraoperative intermittent bolus<br>Drug: Propofol<br>* Intraoperative infusion<br>|
| No Intervention: Standard of Care/Control<br>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 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) Dexmedetomidine infusion (0.4-1.4 mcg/kg/hr) - EEG Guided; Infusion continued till extubation Propofol infusion may be added/used for sedation based on the treating physician's discretion Lidocaine patches Parasternal block (PIFB or Transversus Thoracic Plane Block) on Postoperative day 0 - currently incorporated into standard pain management after surgery based on physician discretion | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in plasma IL-6 levels | Total postoperative increase in IL-6 levels. The increase from baseline to postoperative days 1 and 2 will be quantified and compared between the two groups. | Baseline, postoperative day1 and day 2 | 
| Increase in plasma Neurofilament light levels | Total postoperative increase in Neurofilament light levels. The increase from baseline to postoperative days 1 and 2 will be quantified and compared between the two groups. | Baseline, postoperative day1 and day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concurrent EEG burst suppression and cerebral desaturation | Incidence and cumulative duration of Burst suppression (measured in minutes) will be extracted and quantified from the EEG and Cerebral oximetry records. | Intra-operative | 
| Opioid consumption and postoperative pain control | Total postoperative opioid dose, opioid consumption and pain scores will be quantified and compared between the two groups. The dose will be converted to morphine equivalents for standardization of the outcome and for ease of analysis. Pain will be assessed postoperatively by nursing staff every 4-8 hours and data will be collected form patient's electronic medical records | 48- hours, Postoperative | 
| Burst suppression | 3.) Duration of Burst suppression will be extracted and quantified from the EEG record and compared between both the groups. | Introperative | 
| 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. | Postoperative days till discharge | 
| Cognitive Function | Postoperative cognitive dysfunction at 1- and 6- months will be assessed with telephone version of the Montreal Cognitive Assessment (t-MoCA). It has a total score of 22 and higher score means better cognitive function. | Patients will be assessed for delirium at 1 month and 6 months following the date of surgery | 
| 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. | Intra-operative | 
| Hemodynamic Stability - Systolic Blood pressure (SBP) | Amount of time the systolic blood pressure was above 130 mmHg or below 90 mmHg will be collected from the intra-operative record and medical records to be quantified and compared. | Intraoperative | 
| Hemodynamic Stability - Mean Arterial Blood pressure | Measurement of area under the 65 mmHg mean arterial blood pressure curve will be collected from the intraoperative record and medical records to be quantified and compared. | Intra-operative | 
| Hemodynamic Stability - Coefficient of variation of Mean Arterial BP | Coefficient of variation of mean arterial blood pressure will be collected from the intra-operative record and medical records to be quantified and compared. | Intraoperative | 
| Surgical and delirium markers - Plasma Cortisol | Blood samples will collected, stored, and analyzed at three time points to measure changes in plasma cortisol through the peri-operative course. Plasma cortisol (mcg/dl) will be quantified at baseline, end of bypass, and end of surgery. | Baseline, and till end of surgery |