Better Preserving Brain Health in Elderly Patients Undergoing General Anesthesia

Amanda Decimo, RN, MSN, MPH

An innovative team of researchers, Drs. S. Kendall Smith, Phillip Vlisides, and Miles Berger, navigated the mysteries of neuroscience in the session, “Novel Approaches to Elucidating the Pathophysiology of Perioperative Neurocognitive Disorders,” held on Saturday, March 19 at the IARS 2022 Annual Meeting. The expert panel revealed new technologies and strategies to address one of anesthesia’s most urgent public health concerns: Can we better preserve brain health in our elderly patients who undergo general anesthesia?

The first presenter S. Kendall Smith, MD, PhD, Assistant Professor, Anesthesiology at the Washington University School of Medicine in St. Louis and 2021 IARS Mentored Research Award Recipient, shared her current research that aims to characterize transcriptomic rhythms in older adults undergoing elective cardiac surgery and evaluate relationships with postoperative delirium severity.

Dr. Smith’s research uses blood samples measured with the TimeSignature algorithm to assess molecular mechanisms of circadian rhythm disruptions. This cutting-edge algorithm uses a machine-learning approach that accurately predicts internal circadian time from gene expression in human blood.

In her presentation, she referenced the 2017 Nobel Peace Prize in Physiology or Medicine Recipients, Drs. Jeffrey C. Hall, Michael Rosbash and Michael W. Young, who elucidated the machinery behind this internal molecular circadian clock. This clock system synchronizes central and peripheral organs with molecular rhythms.

Postoperative delirium commonly affects older adults undergoing major surgery. Dr. Smith’s preliminary results show that molecular rhythms are in fact acutely disrupted on day one following cardiac surgery. She may also have identified several emerging patient phenotypes: early larks and night owls. This phenotyping in older adults may allow estimation of internal circadian phase shifts perioperatively that could predict postoperative delirium.

Moving forward, Dr. Smith hopes to explore relevance of this work to postoperative delirium and other perioperative neurocognitive disorders.

Brain health in surgical patients is a hot topic in anesthesia today. Phillip Vlisides, MD, Assistant Professor in Anesthesiology and Executive Director of Neuroscience Research in the Department of Anesthesiology at University of Michigan Medicine, addressed this area with his presentation on “Over-Caffeinated: The Role of Caffeine in Boosting Neural Criticality to Reduce Delirium Risk.”

Dr. Vlisides discussed the problematic perioperative triad leading to increased delirium and cognitive dysfunction. The interrelated cycle of pain, sleep disturbance, and opioid use following surgery propagates delirium. He proposed that caffeine as a potential adjunct might decrease pain and disrupt this triad of delirium and cognitive dysfunction.

Preliminary data from one study suggests caffeine may have acute antinociceptive properties and reduce hyperalgesia for up to a week after surgery. Dr. Vlisides’ study (Vlisides, Anesth Analg 2021) randomized 60 laparoscopic patients to 200mg IV caffeine or placebo groups and measured opioid consumption in the first 3 postoperative days. The randomized group with caffeine required more pain medication, contradicting his study hypothesis. He suggested these patients were more alert in recovery and thus better verbalized pain medication request to nurses. Despite receiving more pain medication, the caffeine group did show less postanesthesia care unit (PACU) delirium, using a screening tool and electroencephalogram (EEG) measurements of frontal-parietal connectivity.

Neuro criticality is defined as the state of a system when it is poised to dynamically shift based on external stimuli or input, Dr. Vslides explained. Imagine an avalanche that collapses at the critical last drop of snow. In neuro criticality, the brain is poised on collapsing to a state of delirium postoperatively. The brain may exhibit a protective shift through different states preventing delirium.

EEG-based biomarkers are being examined as a measure of criticality and their association with PACU delirium. The biomarkers are autocorrelation function and topology phase lag entropy. In phase lag entropy, anterior to posterior asymmetry correlates strongly with criticality (Lee et al, Neuroimage 2018). In Dr. Vlisides’ secondary analysis, nondelirium patients maintained better symmetry in phase lag entropy versus delirium patients who showed asymmetry (Kim H et el Front Hum Neuroscience 2021). Symmetry was also better preserved in caffeinated versus placebo patients.

Dr. Vlisides is still in the hypothesis generating phase of this work with neuro criticality and EEG biomarkers. His team will continue to enhance scientific understanding of the complex pathophysiology behind delirium during the course of their research.

The final presenter Miles Berger, MD, PhD, Associate Professor of Anesthesia at Duke University, addressed “A Show About Nothing: The Role of Altered Default Mode Activity and Connectivity in Delirium and Perioperative Neurocognitive Disorders” during his presentation.

One study (Inouye et al Alz Dementia, 2016) performed cognitive testing and delirium screening postoperatively and found that while patients with acute, postoperative delirium recover, they developed worse cognitive decline three years later. Similarly, an earlier study (Newman MF et al, NEJM, 2001) showed surgical patients with initial postoperative cognitive decline recovered, but then displayed worse long-term cognitive decline three to five years later. Dr. Berger and other researchers conclude that delirium and postoperative dysfunction actually exist on a spectrum of the same pathology.

The Default Mode Network (DMN) is a set of brain regions that are task-negative. They show increased activity patterns when a person is awake but not completing a cognitive task. The DMN regions lie midline and symmetrically. Activity is reduced in these regions with Alzheimer Disease and mild cognitive impairment (Rombouts S, Hum Brain Mapp, 2005).

Another study (Haggstrom LR et al Journal Cerebral Blood Flow & Metabolism, 2017) used PET to show profound hypoactivity in DMN regions during delirium that improved after delirium resolution. The investigators also identified the posterior cingulate as the key hub of DMN activity.

In another study (Choi et al Am J Psychiatry, 2012), the researchers used functional MRI, where the brain is visualized in 3mm cubes, to measure connectivity strength between DMN regions that exhibit strong connectivity with normal DMN activity. The study found greater connectivity strength in the two major DMN hubs (posterior cingulate and precuneus regions) in patients without delirium. In patients with severe delirium, they found significantly less connectivity.

Dr. Berger’s study (Browndyke & Berger et al JAGS 2017) found that patients displaying cognitive dysfunction after cardiac surgery showed less connectivity in the posterior cingulate region using functional MRI. His task-based study (Browndyke & Berger et al Hum Brain Mapp 2018) used a cognitive test with playing cards called N-back. The task-negative DMN region is expected to function when there is no activity; however, a paradoxical effect was seen in surgical patients with increased activity in DMN regions of surgical patients while performing the cognitive test, Dr. Berger explained.

Dr. Berger’s team continues to research causes in the DMN activity changes that occur with anesthesia and delirium. His group is currently exploring mechanisms of neuroinflammation.