Pediatric Anesthesiology 2018 Reviews
Sunday Session II
Updates from SPA Young Investigator Research Award Recipients
Reviewed by Constance L. Monitto, MD
Charlotte Bloomberg Children’s Center
Johns Hopkins Medical Institutions
Charles B. Berde, MD, PhD (Boston Children’s Hospital) introduced the presentations by this year’s Society for Pediatric Anesthesia Young Investigator Research Grant recipients. The focus of all three investigators involved anesthesia-related neurotoxicity, but each took a unique approach to this important topic.
James O’Leary, MM, MD (The Hospital for Sick Children, Toronto) presented his research titled “The Effect of Surgery on Child Development at Primary School Entry: A sibling-controlled cohort study.” The aim of Dr. O’Leary’s study was to use the Early Development Instrument, a validated teacher-completed questionnaire used to assess child development at primary school entry in Ontario, in conjunction with population-based health and demographic data to investigate whether anesthesia and surgery in early childhood are associated with adverse child development.
Starting with over 250,000 unique records, Dr. O’Leary identified 2,346 sibling pairs in which only one child underwent surgery. Comparing these pairs, he determined that those who underwent surgery were significantly more likely to be male and the eldest child. Most surgeries were day surgery and the majority were ENT, urologic, or musculoskeletal. Dr. O’Leary reported that after mitigating for biological vulnerability and environmental factors, exposure to surgery in early childhood was not associated with an increased risk of adverse child development. In discussing his findings, he reported that his results are consistent with both the prior PANDA study and data from the Netherlands Twin registry. Limitations of his work included a lack of generalizability as most children had only one exposure to surgery.
The second recipient, Michael Montana, MD, PhD (Washington University in St. Louis), discussed his research project “A potential role for neurosteroid anesthesia in protection from anesthetic neurotoxicity.” Dr. Montana began his presentation by reminding the audience of our current practice limitation that all commonly used general anesthetics have been implicated as neuroapoptogenic in animal models. He then reviewed previous studies demonstrating that neurosteroids, compounds which modulate NMDA and GABAa neuronal activity, can be neuroprotective.
While some of these compounds are non-GABAergic and nonsedating, alfaxalone, a GABAergic neurosteroid, has anesthetic properties as well. Used outside the US in 1970’s and 1980’s, alfaxalone has a rapid onset, short duration of action, and minimal cardiopulmonary effects. Furthermore, it ameliorates neuronal apoptosis in fetal sheep. Unfortunately, anaphylactic and hypersensitivity reactions thought to be due to its solvent led to its withdrawal from the market in the 1980’s. More recently, however, the drug has been reformulated, dissolved in a beta-cyclodextrin, and this new solvent is being evaluated in humans. The drug’s availability as a veterinary anesthetic led Dr. Montana and his colleagues to investigate it further in order to determine whether an anesthetic dose of alfaxalone will induce less neuroapoptosis than the commonly used intravenous anesthetic, propofol. Studying P7 neonatal mice administered intraperitoneal injections of vehicle, propofol, or alfaxalone, Dr. Montana found that propofol, but not alfaxalone, increased activated caspase 3 staining, an indicator of neuronal apoptosis.
Based on this promising initial result, future studies planned by Dr. Montana and his co-investigators include examining the effect of higher or repeated alfaxalone doses, behavioral studies, and studying the drug in larger species to allow for intravenous drug dosing.
The final presentation was by Emmett E. Whitaker III, MD (University of Vermont Larner College of Medicine, Burlington), who presented pilot data on “Surgical Stress-Induced Glutamate Dysregulation in Prefrontal Cortex of Neonatal Piglets.” Dr. Whitaker began his presentation by discussing how NMDA receptor overstimulation can lead to oxidative stress, mitochondrial dysfunction and neuronal apoptosis. However, while it is believed that both anesthesia and surgery can lead to changes in glutamate regulation resulting in toxicity, because the two generally go hand-in-hand, it is unclear what the role of each is individually.
This uncertainty has spurred Dr. Whitaker and colleagues to develop an in vivo piglet model using enzyme-linked microelectrode arrays to study glutamate dynamics in the juvenile animal brain. In his pilot study, three male and three female three-day old piglets were anesthetized, instrumented, and underwent an osteotomy to mimic surgical stress. Glutamate activity was continuously measured and preliminary data demonstrated significantly more glutamate activity in the presence of surgical stress as compared to sevoflurane alone, suggesting a critical role for surgical stress in glutamate modulation. While these initial studies were short-term, Dr. Whitaker reported that a goal of future studies involves development of a chronically instrumented piglet model to allow for longer term monitoring.
