Quenching the Cognitive Fire of Surgery: New Insights into the Mechanisms, Biomarkers and Mitigation Strategies for Perioperative Neurocognitive Disorders

Christian S. Guay, MD

Leading experts came together to discuss the latest advancements in understanding and preventing perioperative neurocognitive disorders (PND), during the symposium titled “Targets for Prevention of Perioperative Neurocognitive Disorders: What’s New in Town?” co-sponsored by the Society for the Advancement of Geriatric Anesthesia (SAGA), at the 2024 Annual Meeting, presented by IARS and SOCCA, on Saturday, May 18.

Lizbeth Evered, MSc, PhD, associate professor at Weill Cornell Medicine, began by addressing the prevalence of perioperative neurocognitive disorders, which are the most frequent complications in older individuals undergoing surgery. She reviewed updated nomenclature that aligns with various specialties, categorizing PND into four distinct phases: postoperative delirium (during hospital admission), delayed neurocognitive recovery (dNCR) up to 30 days postoperatively, postoperative neurocognitive disorders (mild and major) from 1 to 12 months postoperatively, and mild and major neurocognitive disorders beyond 12 months.

Postoperative delirium is particularly common, with an incidence ranging from 5% to 60%, with cardiac surgery associated with the highest incidence. Up to 75% of cases go unrecognized, primarily due to hypoactive delirium. Dr. Evered emphasized several modifiable risk factors for PND, including frailty, polypharmacy, and lifestyle factors such as exercise, nutrition, and sleep. Mitigation strategies highlighted included cognitive prehabilitation and strong recommendations for physical activity, tobacco cessation, and nutritional interventions. Interestingly, regional anesthesia does not reduce the incidence of delirium compared to general anesthesia, suggesting that the effects of surgery itself might overwhelm those of the type of anesthesia used. The use of dexmedetomidine in the ICU was noted to decrease the incidence of delirium. While EEG-guided light anesthesia may reduce the incidence of postoperative delirium, meta-analyses suggest that this effect is fragile. Total intravenous anesthesia (TIVA) might decrease early postoperative delirium compared to inhaled anesthesia, though better-designed studies are needed to confirm this, and are currently underway.

Dr. Evered summarized that perioperative neurocognitive disorders are common and that the magnitude of the inflammatory response does not differ between inhaled and intravenous anesthesia. Nonpharmacological interventions remain the best practice, with multicomponent care bundles being most effective.

David A. Scott, MBBS, FANZCA, PhD, professor in the department of critical care at University of Melbourne, followed with a presentation focusing on the role of biomarkers in predicting, diagnosing, and resolving PND. He emphasized the importance of biomarkers that are easy to access, reliable, sensitive, specific, and quantifiable. These biomarkers provide critical insights into the underlying mechanisms of PND, helping clinicians “look under the hood” to understand the complex pathophysiology.

Dr. Scott outlined the possible pathophysiology of PND, explaining that surgery and anesthesia induce peripheral inflammation. This inflammation can lead to a leaky blood-brain barrier, resulting in neuroinflammation, glial activation, and neuronal damage, which manifest as PND. A brain already vulnerable due to primed microglia increases the risk of PND from perioperative neuroinflammation. The pathophysiology and associated biomarkers can be categorized into three stages: predictive preoperative biomarkers, postoperative disorder biomarkers, and resolution biomarkers.

Among the key biomarkers discussed, IL-6 is widely used for monitoring lymphocytes, and TNF-alpha for macrophages. CRP is another important biomarker, although it peaks slower, taking one to two days to rise and over a week to resolve. In the preoperative phase, elevated levels of baseline IL-6, especially in trauma and cardiac surgery patients, are associated with a higher risk of postoperative delirium. TNF-alpha and CRP also serve as valuable preoperative biomarkers. Alzheimer biomarkers, such as neurofilament light (NfL), traditionally measured in cerebrospinal fluid but now detectable in blood, were highlighted for their association with POD. NfL levels indicate neuronal damage and are linked to postoperative delirium.

During surgery, systemic inflammatory responses are proportional to surgical stress (i.e. highest in cardiac surgery), with markers like IL-6, IL-10, and TNF-alpha rising quickly, while CRP peaks more slowly. No differences have been observed in inflammatory responses between TIVA and inhaled anesthesia. Postoperative increases in IL-6 and Alzheimer biomarkers correlate with cognitive function decline at three months.

Dr. Scott concluded that surgery is associated with increased blood inflammatory and neural injury biomarkers, proportional to surgical trauma. Baseline risk factors for PND include pre-existing cognitive impairment (indicated by Alzheimer biomarkers such as Aβ42), inflammatory upregulation (evidenced by IL-6 and CRP), and neuronal injury (indicated by NfL). Future directions for research include exploring new biomarkers through metabolomics, which could provide deeper insights into the biochemical changes associated with PND. Despite initial hopes, studies on the use of dexamethasone to mitigate PND have yielded disappointing results, underscoring the need for further investigation into effective interventions.

Roderic Eckenhoff, MD, Austin Lamont Professor of Anesthesia, University of Pennsylvania Perelman School of Medicine, concluded the session by exploring the question of whether anesthetics can influence PND. He noted that studies like RAGA and REGAIN found no difference in delirium incidence between regional and general anesthesia, though sedation during spinal anesthesia could confound results. The addition of midazolam to propofol for ICU sedation increases delirium incidence, whereas dexmedetomidine appears protective. He also highlighted a fascinating study showing that anesthesia with 1 MAC of sevoflurane for two hours in volunteers aged 40-80 not undergoing surgery resulted in no delirium and rapid cognitive recovery, further reinforcing the idea that surgical trauma is the main driver of PND. Regarding major neurocognitive disorders beyond 30 days, large database studies showed no difference in dementia-free survival between patients who had general or regional anesthesia. Interestingly, patients who underwent appendectomies had a lower incidence of dementia, likely due to confounding factors.

Searching for a common mechanism underlying the potential benefits of propofol and dexmedetomidine, Dr. Eckenhoff pointed to their shared ability to reduce intraneuronal calcium levels. Elevated intraneuronal calcium is associated with neurodegeneration, and both propofol and dexmedetomidine reduce calcium levels, potentially mitigating neurodegeneration. A recent study showed that propofol inhibits RyR-1, whereas inhaled anesthetics can induce it. Interestingly, prescribed brain-permeant calcium channel blockers have been associated with a lower incidence of delirium and dementia. Dantrolene is also a potential therapeutic option for future studies targeting this mechanism.

Dr. Eckenhoff concluded that while results in POD do not always correlate with those in delayed neurocognitive disorder or major neurocognitive disorder, suggesting different underlying mechanisms, there is weak evidence for any class of anesthetics interacting with PND mechanisms to change acute or long-term cognitive outcomes. However, targeting intraneuronal calcium perioperatively may offer a promising approach to reducing PND.

This symposium provided a comprehensive overview of the current understanding and strategies for tracking and preventing perioperative neurocognitive disorders. While nonpharmacological interventions and multicomponent care bundles remain the best practices, there is a need for more research into the effects of different anesthetics and the potential protective effects of targeting intraneuronal calcium. The insights gained from biomarkers and mechanistic studies offer promising avenues for future research and improved patient outcomes.