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

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

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

Study Overview

• Status: Completed
• Conditions: Pain; Postoperative Delirium; Neurocognitive Dysfunction; Hemodynamic Instability
• Intervention / Treatment: Device: EEG Monitoring; Drug: Ropivacaine; Drug: Ketamine; Drug: Remifentanil; Drug: Dexmedetomidine; Drug: Rocuronium; Drug: Propofol

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Multimodal General Anesthesia (MMGA Bundle) - EEG Guided; 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 protocolIV AcetaminophenIV Hydromorphone/fentanyl boluses as needed per current practice for rescue analgesiaOther 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; Perioperative monitoring, MMGA guided by EEG for intervention group; Other Names: Sedline Monitoring; Drug: Ropivacaine; 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); Drug: Ketamine; Intraoperative infusion; Drug: Remifentanil; Intraoperative infusion; Drug: Dexmedetomidine; Intraoperative infusion; Drug: Rocuronium; Intraoperative intermittent bolus; Drug: Propofol; Intraoperative infusion
No Intervention: 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; Standard pain management protocolIV Acetaminophen (1 gram) x 4 doses at 6 hour intervals starting from 1 hr after ICU arrivalIV Hydromorphone/fentanyl boluses as needed per current practice for rescue analgesiaOther 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?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, postoperative day 1, and postoperative day 2
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.	Baseline, postoperative day 1, and postoperative day 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From end of surgery to 48 hours postoperatively
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.	From end of surgery to 48 hours postoperatively
Burst Suppression	Duration of burst suppression was extracted and quantified from the intraoperative EEG record and compared between the MMGA and control groups.	intraoperative period, from anesthetic induction until the end of surgery
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.	From postoperative day 1 until hospital discharge, an average of 4 days
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.	Patients will be assessed for cognitive function 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.	Intraoperative period, from induction of anesthesia until transfer from the operating room

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Balachundhar Subramaniam, MD,MPH,FASA, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med. 2010 Dec 30;363(27):2638-50. doi: 10.1056/NEJMra0808281. No abstract available.
• Mulier J. Opioid free general anesthesia: A paradigm shift? Rev Esp Anestesiol Reanim. 2017 Oct;64(8):427-430. doi: 10.1016/j.redar.2017.03.004. Epub 2017 Apr 18. No abstract available. English, Spanish.
• Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. N Engl J Med. 2017 Jul 27;377(4):391-394. doi: 10.1056/NEJMsr1706626. Epub 2017 May 31. No abstract available.
• MacKenzie KK, Britt-Spells AM, Sands LP, Leung JM. Processed Electroencephalogram Monitoring and Postoperative Delirium: A Systematic Review and Meta-analysis. Anesthesiology. 2018 Sep;129(3):417-427. doi: 10.1097/ALN.0000000000002323.
• 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.
• Berger M, Terrando N, Smith SK, Browndyke JN, Newman MF, Mathew JP. Neurocognitive Function after Cardiac Surgery: From Phenotypes to Mechanisms. Anesthesiology. 2018 Oct;129(4):829-851. doi: 10.1097/ALN.0000000000002194.
• Brown EN, Pavone KJ, Naranjo M. Multimodal General Anesthesia: Theory and Practice. Anesth Analg. 2018 Nov;127(5):1246-1258. doi: 10.1213/ANE.0000000000003668.
• Nicolini F, Agostinelli A, Vezzani A, Manca T, Benassi F, Molardi A, Gherli T. The evolution of cardiovascular surgery in elderly patient: a review of current options and outcomes. Biomed Res Int. 2014;2014:736298. doi: 10.1155/2014/736298. Epub 2014 Apr 10.
• Maheshwari K, Ahuja S, Khanna AK, Mao G, Perez-Protto S, Farag E, Turan A, Kurz A, Sessler DI. Association Between Perioperative Hypotension and Delirium in Postoperative Critically Ill Patients: A Retrospective Cohort Analysis. Anesth Analg. 2020 Mar;130(3):636-643. doi: 10.1213/ANE.0000000000004517.
• Ni K, Cooter M, Gupta DK, Thomas J, Hopkins TJ, Miller TE, James ML, Kertai MD, Berger M. Paradox of age: older patients receive higher age-adjusted minimum alveolar concentration fractions of volatile anaesthetics yet display higher bispectral index values. Br J Anaesth. 2019 Sep;123(3):288-297. doi: 10.1016/j.bja.2019.05.040. Epub 2019 Jul 3.
• Shanker A, Abel JH, Narayanan S, Mathur P, Work E, Schamberg G, Sharkey A, Bose R, Rangasamy V, Senthilnathan V, Brown EN, Subramaniam B. Perioperative Multimodal General Anesthesia Focusing on Specific CNS Targets in Patients Undergoing Cardiac Surgeries: The Pathfinder Feasibility Trial. Front Med (Lausanne). 2021 Oct 14;8:719512. doi: 10.3389/fmed.2021.719512. eCollection 2021.
• Hesse S, Kreuzer M, Hight D, Gaskell A, Devari P, Singh D, Taylor NB, Whalin MK, Lee S, Sleigh JW, Garcia PS. Association of electroencephalogram trajectories during emergence from anaesthesia with delirium in the postanaesthesia care unit: an early sign of postoperative complications. Br J Anaesth. 2019 May;122(5):622-634. doi: 10.1016/j.bja.2018.09.016. Epub 2018 Oct 25.
• Mahanna-Gabrielli E, Schenning KJ, Eriksson LI, Browndyke JN, Wright CB, Culley DJ, Evered L, Scott DA, Wang NY, Brown CH 4th, Oh E, Purdon P, Inouye S, Berger M, Whittington RA, Price CC, Deiner S. State of the clinical science of perioperative brain health: report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018. Br J Anaesth. 2019 Oct;123(4):464-478. doi: 10.1016/j.bja.2019.07.004. Epub 2019 Aug 19.

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2023
• Primary Completion (Actual): June 30, 2024
• Study Completion (Actual): December 31, 2024

Study Registration Dates

• First Submitted: February 14, 2022
• First Submitted That Met QC Criteria: March 4, 2022
• First Posted (Actual): March 15, 2022

Study Record Updates

• Last Update Posted (Actual): November 26, 2025
• Last Update Submitted That Met QC Criteria: November 24, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Emergence Delirium; Pain; Cognition Disorders; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Acids, Acyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Polycyclic Compounds; Imidazoles; Anilides; Amides; Aniline Compounds; Amines; Piperidines; Steroids; Fused-Ring Compounds; Phenols; Benzene Derivatives; Androstanes; Propionates; Androstanols; Remifentanil; Ropivacaine; Rocuronium; Dexmedetomidine; Propofol; Ketamine
• Other Study ID Numbers: 2021-P-000889

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes