Measuring, Reproducing and Phenotyping Anesthetic Neurotoxicity: Insights from Intraoperative Neuromonitoring and the MASK Study

Neurotoxic effects of anesthetics in pediatric patients is currently one of the most hotly debated topics in the anesthesiology literature. Preclinical data in animal models seems to suggest a causal effect on both the histological and behavioral levels. However, this data is not always reproducible in animals and almost impossible to replicate in humans due to ethical and experimental considerations. Santhanam Suresh, MD, Patrick L. Purdon, PhD, Beverley A. Orser, MD, PhD, FRCPC, and David O. Warner, MD, helped shed some light on this controversial topic using three different perspectives.

Furthermore, the generalized increase in EEG power during GABAergic anesthesia correlates with inhibitory dendritic spine density in human prefrontal cortex, increasing during the first few years of life and then decreasing as we age. This age-dependent phenomenon closely resembles the curves describing critical periods of plasticity: transient windows during brain development when children have the capacity to learn new skills at astounding rates. In fact, it has been suggested that cortical inhibition (e.g. with propofol) may shift these critical periods to earlier ages, and cortical excitation (e.g. with ketamine) could shift them to later ages, although this remains to be born out with experimental data. In summary, because GABA interneurons play a key role in brain development, the dynamic EEG changes observed during pharmacological modulation of GABA tone may offer non-invasive insights into the developing human brain.

Finally, Dr. Warner shared the results of the MASK study, an observational, population-based propensity-matched study with retrospective and prospective components. Retrospectively, it was found that learning disabilities were more frequent in children who had multiple, but not single exposures to anesthesia prior to the age of three. Similar results were reported for ADHD and group-administered achievement and ability tests. Prospectively, they sought to describe the phenotypes of anesthesia-associated neurotoxicity in humans. Multiple psychometric assessments and parent reports were used to describe the phenotypes of children who were exposed to anesthesia once or multiple times. The primary outcome, the WASI full scale IQ, was found not to be different between unexposed, singly-exposed and multiply-exposed children. However, children with multiple exposures did exhibit mildly impaired performance on a fine motor composite score and processing speed. Furthermore, parents subjectively reported impaired reading and executive function in both singly and multiply-exposed children. Although these results alone do not imply causation, they add much-needed human data to the neurotoxicity literature and will help focus future preclinical studies and clinical trials.