Perioperative Multimodal General Anesthesia Focusing on Specific CNS Targets in Patients Undergoing Cardiac Surgeries: The Pathfinder Feasibility Trial

Abstract

Multimodal general anesthesia (MMGA) is a strategy that utilizes the well-known neuroanatomy and neurophysiology of nociception and arousal control in designing a rational and clinical practical paradigm to regulate the levels of unconsciousness and antinociception during general anesthesia while mitigating side effects of any individual anesthetic. We sought to test the feasibility of implementing MMGA for seniors undergoing cardiac surgery, a high-risk cohort for hemodynamic instability, delirium, and post-operative cognitive dysfunction. Twenty patients aged 60 or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries were enrolled in this non-randomized prospective observational feasibility trial, wherein we developed MMGA specifically for cardiac surgeries. Antinociception was achieved by a combination of intravenous remifentanil, ketamine, dexmedetomidine, and magnesium together with bupivacaine administered as a pecto-intercostal fascial block. Unconsciousness was achieved by using electroencephalogram (EEG)-guided administration of propofol along with the sedative effects of the antinociceptive agents. EEG-guided MMGA anesthesia was safe and feasible for cardiac surgeries, and exploratory analyses found hemodynamic stability and vasopressor usage comparable to a previously collected cohort. Intraoperative EEG suppression events and postoperative delirium were found to be rare. We report successful use of a total intravenous anesthesia (TIVA)-based MMGA strategy for cardiac surgery and establish safety and feasibility for studying MMGA in a full clinical trial. Clinical Trial Number: www.clinicaltrials.gov; identifier NCT04016740 (https://ichgcp.net/clinical-trials-registry/NCT04016740).

Keywords: EEG; analgesia; cardiac; multimodal; neuroanesthesia; nociception; regional; suppression.

Conflict of interest statement

Masimo Corporation has licensed and paid royalties on intellectual property to Massachusetts General Hospital created by EB. He is also a cofounder of PASCALL, a company developing closed loop physiological control systems for anesthesiology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Shanker, Abel, Narayanan, Mathur, Work, Schamberg, Sharkey, Bose, Rangasamy, Senthilnathan, Brown and Subramaniam.

Figures

Figure 1

Schematic depictions of multimodal general anesthesia protocol split into individual components for anesthetic plan. (A) Nociceptive stimuli are managed with local and systemic anitinociceptives. This strategy leverages complementary mechanisms of each antinociceptive drug to achieve inhibition of nociceptive responses locally, at sites within the spinal cord, and at sites in the brain stem. (B) Decreased arousal (unconsciousness) is generated primarily via propofol potentiation of GABAergic inhibitory neurotransmission. The antinociceptive agents we selected have secondary effects in cortical or brain stem regions and contribute to decreased arousal. (C) Cardiopulmonary bypass (CPB) and anesthetic agents affect hemodynamic stability during cardiac surgery. Administration of propofol causes bradycardia and hypotension, and the anesthesiologist will guide administration of vasopressors to compensate for these changes. Importantly, CPB eliminates heart rate and pulsatile blood flow, causing the anesthesiologist to rely on mean arterial blood pressure to guide vasopressor dosing. This also eliminates the ability to use heart rate as a signal of patient response to painful stimuli.

Figure 2

Ultrasound image of the chest wall showing anterior chest wall structures at the level of 4th Intercostal space. PMM, Pectoralis major muscle, ICM, Intercostal Muscles, R4, Fourth rib, R5, Fifth rib, Shows the position of needle, pleura and lung parenchyma.

Figure 3

Quantification of hemodynamic stability and vasopressor usage during MMGA in comparison to a historical standard-of-care. Little difference was observed between hypotensive AUC (median, [IQR] min'mmHg; MMGA 921.0, [793.1, 1287.2]; historical 995.1, [653.7, 1292.7]; P = 0.72 Mann-Whitney U test), CV (median, [IQR]; MMGA 0.32, [0.28 0.36]; historical 0.34, [0.31, 0.38]; P = 0.14 Mann-Whitney U test), and norepinephrine equivalent dose (median, [IQR] mcg; MMGA 734.5, [526.1, 856.1]; historical 704.77, [336.4 1065.0], P = 0.90 Mann-Whitney U test).

Figure 4

Annotated recordings from one cardiac surgery using MMGA. (A) Computed EEG spectrogram for a selected MMGA cohort patient during cardiac surgery with labeled timepoints of surgical incision (S), sternotomy (ST), heparin bolus (H), bypass begin (BB), bypass end (BE), and sternal closure (CS) before ICU transfer. Suppression events are shown below spectrogram. (B) EEG spectrogram for a control cohort patient labeled as in (A). (C) Selected 60s EEG epochs comparing a waveform during general anesthesia with a waveform during burst suppression, a coma-like deeper state of anesthesia. (D) Distribution of the of time spent in suppression from induction to anesthesia end for the MMGA (n = 18, median suppression time = 4.24 min, IQR [1.87, 7.33]) and control (n = 2, suppression times 13.56 min and 8.35 min) cohorts.