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: Recruiting
• 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 (Estimated): 70
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Balachundhar Subramaniam, MD,MPH,FASA; Phone Number: 617-667-2721; Email: sadhgurucenter_research@bidmc.harvard.edu
• Study Contact Backup: Name: Sepideh Hariri, Phd; Email: sadhgurucenter_research@bidmc.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Balachundhar Subramaniam, MD,MPH; Phone Number: 617-667-2721; Email: sadhgurucenter_research@bidmc.harvard.edu
      • Principal Investigator: Balachundhar Subramaniam, MD,MPH

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	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
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
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

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.
• 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. Erratum In: Br J Anaesth. 2019 Dec;123(6):917.
• 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.
• 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. Erratum In: Br J Anaesth. 2019 Aug;123(2):255.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2023
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): November 1, 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): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Delirium; Cognitive Dysfunction; Emergence Delirium; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Anesthetics, Local; Neuromuscular Agents; Neuromuscular Nondepolarizing Agents; Neuromuscular Blocking Agents; Ketamine; Remifentanil; Propofol; Dexmedetomidine; Ropivacaine; Rocuronium
• 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