The Daily Dose • Friday, May 17

Anesthesia and the Nervous System: Inflammation, Toxicity and Monitoring

By Christian S. Guay, MD, from the IARS, AUA and SOCCA 2019 Annual Meetings*

Neuroinflammation is emerging as an important factor driving postoperative cognitive dysfunction, and dexmedetomidine as a CNS anti-inflammatory agent with features of sleep biomimicry. Early anesthetic exposure in non-human primate newborns is associated with gliosis, as measured via GFAP staining in the visual cortex. During periods of inactivity, the EEG of human infants receiving spinal anesthesia without sedatives resembles natural N2 sleep. The fourth and final AUA Scientific Advisory Board Oral Session focused on the neurological system, from neuroinflammation in postoperative cognitive disorders (POCD) to pediatric neurotoxicity and EEG during spinal anesthesia.

The first presentation featured results of the ongoing INTUIT study, presented by Mr. Thomas Bunning, under the mentorship of Dr. Miles Berger. The study, “The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Neurocognitive Dysfunction and Delirium in Older Adults,” is based on the premise that neuroinflammation is one of several interacting factors contributing to POCD. Specifically, their aims are to describe the expression of monocytes and MCP-1 in cerebrospinal fluid (CSF) of patients during the perioperative period, and to investigate whether these inflammatory markers are associated with POCD and changes in the default mode network. The study is currently underway and actively enrolling patients. The preliminary data presented suggests that the ratio of monocytes to lymphocytes in the CSF increases in patients who develop POCD.

Dr. Mervyn Maze followed the INTUIT study with results from a preclinical study, which also focused on neuroinflammation and POCD, with the added intervention of dexmedetomidine (Dex). Dr. Maze opened his talk, “Dexmedetomidine Prevents Lipopolysaccharide (LPS)-induced Neuroinflammation and Cognitive Decline through an α2A Adrenoceptor Mechanism in Mice,” with a brief review of the synaptic hypothesis for sleep and shared mechanisms of action between natural sleep and Dex, namely activation of the VLPO. In the presented study, mice were administered LPS to activate their systemic immune system and induce a model of POCD. In a classic pharmacological design, a subset of mice were pretreated with alpha-2 antagonists or a control, before receiving Dex, an alpha-2 agonist. In this way, Dr. Maze showed that Dex reverses POCD and decreases hippocampal IL-1 in this mouse model, and furthermore that these effects are lost in the setting of alpha-2 antagonism. These results can help inform future clinical trials aiming to decrease the incidence of POCD.

Next, Dr. Viola Neudecker presented results from a study in a rapidly growing and debated field: anesthetic neurotoxicity in pediatric brains. Her study, “GFAP Expression in the Visual Cortex is Increased in Juvenile Non-Human Primates that were Exposed to Anesthesia during Infancy,” focused on GFAP staining of non-human primate visual cortex, as a marker of gliosis. Non-human primates received one of three treatments in the newborn period, with the anesthetic of choice being 1.8% isoflurane for 5 hours: 1. anesthetic exposure during the sixth day of life; 2. anesthetic exposure during the sixth, ninth and twelfth days of life; or 3. no anesthetic exposure (30% oxygen control). Histopathological staining of primary V1 revealed that participants in the anesthetic exposure groups had increased GFAP expression compared to the control group. Dr. Neudecker concluded that GFAP may serve as a novel histopathological marker for anesthetic neurotoxicity in infants.

The final speaker, Dr. Emmett Whitaker, presented his group’s work on the EEG signatures of spinal anesthesia. The purpose of the presented study, “The Electroencephalographic Signature of Spinal Anesthesia in Infants: A Multi-Center Pilot Study,” was to investigate a curious phenomenon whereby infants who receive spinal anesthesia without any sedatives often exhibit signs of sleepiness/sedation. Previous studies had showed that these changes in level of consciousness were associated with decreasing processed EEG indexes. However, the actual EEG dynamics had not been reported. To further study the electrophysiology of this phenomenon, the investigators analyzed the raw and frequency-transformed perioperative EEG of pediatric patients (< 1 y.o.) who received spinal anesthesia (0.2 mg/kg of 0.5% bupivacaine +/- clonidine) without any intravenous or oral sedatives. Interestingly, they found that two-thirds of the infants developed EEG sleep spindles, a hallmark of N2 sleep, as well as global slowing of their EEG. In contrast to most anesthetized brain states, the infants’ EEGs also exhibited a global decrease in power compared to the awake state. These findings suggest that the sedation observed in infants receiving spinal anesthesia likely represents a transition to physiological sleep states. Dr. Whitaker was awarded the Junior Faculty Research Award in Pediatric Anesthesia for his work.

Drs. Maze, Neudecker, Whitaker and Mr. Bunning’s e-Posters are available for viewing at https://tinyurl.com/AM19eposters.

*Coverage from the AUA Scientific Advisory Board Oral Session IV, moderated by Niccolo Terrando, PhD and Paul Garcia, MD, PhD, at the AUA 2019 Annual Meeting

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