Brainwaves, Biomarkers and Behavior: Unraveling the Effects of Anesthesia on Neurodevelopment

Christian S. Guay, MD

At this year’s SmartTots Panel, moderated by Dean Andropoulos, MD, MHCM, leading researchers in pediatric anesthesiology presented recent findings on the neurological effects of anesthesia in young children. The session featured presentations from Viola Neudecker, MD, Ian Yuan, MD, M.Eng. and Dr. Andropoulos himself, each highlighting critical aspects of anesthesia’s impact on neurodevelopment and potential strategies for mitigating risks.

Dr. Neudecker, associate research scientist in the department of anesthesiology at Columbia University Medical Center, kicked off the session with a review of her study on the long-term effects of isoflurane anesthesia on brain connectivity and behavior in pediatric nonhuman primates. Concerns about the neurobehavioral development of children exposed to general anesthetics have spurred numerous studies, but results have been mixed. While human studies suggest general intelligence remains unaffected, behavioral alterations are a significant concern. Dr. Neudecker’s research focused on functional connectivity MRI (fcMRI) in pediatric nonhuman primates (NHPs) exposed to isoflurane, a common anesthetic. Her study involved early-life exposure to 1.8% isoflurane for five hours either once, three times, or not at all (control group). Behavioral and cognitive assessments were conducted at various intervals, culminating in an MRI scan and histopathological examination at two years of age.

The findings were compelling: while there were no significant changes in cognition, memory, or fine motor skills, there were notable behavioral alterations. Specifically, NHPs exposed to isoflurane exhibited less close social behavior. Brain structure analysis revealed increased astrocyte activation, or astrogliosis, particularly in the amygdala, indicating neuroinflammation.

There were also alterations in resting-state functional connectivity between the posterior cingulate cortex and secondary auditory, polar prefrontal, and temporal cortices, and the anterior insula, which correlated with reduced social behaviors and increased astrogliosis. These findings suggest that neonatal exposure to isoflurane disrupts brain connectivity in areas crucial for social behavior, potentially leading to long-term behavioral changes.

Dr. Yuan, a pediatric anesthesiologist at Children’s Hospital of Philadelphia, followed with a presentation examining the interaction of anesthetics with pediatric brains through the lens of electroencephalography (EEG). In one study, investigators monitored 21 neonates undergoing cardiac surgery with deep hypothermic circulatory arrest and categorized their EEGs into different levels of suppression: slow/continuous (i.e., no suppression), mild burst suppression, severe burst suppression and isoelectricity. They found that more significant EEG suppression correlated with lower scores on the Vineland 2 questionnaire, which assesses intellectual and developmental disabilities. Another larger study of 648 infants found that 32% experienced isoelectric EEGs, which were associated with higher doses of sevoflurane, hypotension, and younger age, along with lower quality of life assessments.

Dr. Yuan also highlighted the high prevalence of emergence delirium in children, and the ability of EEG patterns to predict its incidence. Specifically, the presence of interictal spikes during induction, low alpha power during emergence and high delta power during emergence all predict emergence delirium. Considering the EEG’s ability to predict short, medium and long-term effects of anesthesia on pediatric brains, Dr. Yuan advocates for the use of EEG-guided anesthesia in children to titrate the appropriate dose of anesthetics and target specific brain states. One common target is to avoid suppression on the EEG. Spectral edge frequency 95 (SEF95), the frequency below which 95% of EEG power is concentrated, can also be considered as a propofol biomarker and targeted during anesthetic titration. To help provide some guidance to anesthesiologists on appropriate anesthetic depth, he and his team undertook a dose-finding study to determine effective doses to prevent responses to noxious stimuli in 95% of patients (ED95):

• Pacifier placement: ED95 = 19.3 Hz
• Electrical stimulation: ED95 = 10.4 Hz
• Laryngoscopy: ED95 = 5.2 Hz

Dr. Andropoulos, anesthesiologist-in-chief at Texas Children’s Hospital and chair, department of anesthesiology, perioperative, and pain medicine, professor of anesthesiology and vice chair for clinical affairs of the department of anesthesiology at Baylor College of Medicine, concluded the session with a sample of the highly anticipated results of the TREX trial, investigating whether dexmedetomidine, an alpha-2 agonist, can improve neurodevelopmental outcomes when used alongside low-dose sevoflurane in young children.

Dexmedetomidine, well known for its minimal respiratory depression and anti-inflammatory properties, has shown promise as a neuroprotectant in animal studies. The TREX trial, a Phase 3, randomized, active-controlled, parallel group, assessor blinded, multicenter, superiority trial, enrolled children younger than two years undergoing over two hours of general anesthesia. The primary outcome is neurodevelopmental assessment at age three years using the Weschler Full Scale IQ questionnaire. In the control group, the standard sevoflurane dose target was 2.5-3%. In the intervention group, dexmedetomidine and remifentanil infusions were added and the target sevoflurane dose was lowered to below 0.6-0.8%. Enrollment started in August 2017, and ended with a final enrollment of 455 patients, on April 21, 2023.

Preliminary findings from prespecified secondary outcomes revealed that the dexmedetomidine plus low-dose sevoflurane and remifentanil regimen resulted in less hypotension, more bradycardia, and more signs of light anesthesia compared to the traditional dose sevoflurane arm. Recovery assessments also indicated faster recovery. Importantly, no differences in adverse events were observed, demonstrating the feasibility of this anesthetic approach.

The primary neurodevelopmental outcomes are expected in 2026, but these early results offer hope that this dexmedetomidine/remifentanil/low-dose sevoflurane regimen is feasible and effective.

The SmartTots panel shed light on the intricate relationship between pediatric anesthesia and neurodevelopment. Through innovative research and collaborative efforts, scientists like Dr. Neudecker, Dr. Yuan, and Dr. Andropoulos are paving the way for safer anesthetic practices and improved outcomes for the youngest patients. As these studies continue to unfold, they promise to enhance our understanding and guide future clinical practices in pediatric anesthesiology.