SmartTots Panel: The Neurotoxicity Conundrum Unveiled

By Adaora M. Chima, MBBS, MPH, from the IARS, AUA and SOCCA 2019 Annual Meetings*

A palpable sense of relief was evident at the end of the IARS SmartTots Panel, Anesthesia and Neurotoxicity: A Conundrum for Clinicians, on Sunday, May 19, in Montreal. In December of 2016, the U.S Food and Drug Administration issued a warning regarding the neurotoxic effects of general anesthesia and sedating drugs on the developing brain. These findings had been observed in animal models and the translation of these results to the human species had been in question. The SmartTots panel reviewed the science behind this warning, and the results of seminal clinical studies have shown reassuring results regarding the neurological effects of anesthetic drugs on the developing brain. 

Panel members consisted of Jeffrey Sall, PhD, MD, a preclinical scientist at University of California, San Francisco; Mary Ellen McCann, MD, MPH of Harvard University; and Lena Sun, MD, MPH, Professor of Anesthesiology and Pediatrics, Columbia University College of Physicians and Surgeons and SmartTots Medical Officer.

Dr. Sall set the stage by explaining the utility and limitations of different biological models used in preclinical investigations:

• In vitro/culture cells such as neurons and stem cells are useful for answering specific simple questions but have severed connections and transferability is unclear.
• In vivo models which range from nonmammalian species, small mammals (rodents), to nonhuman primates, which have different degrees of complexity and relatability to the human species. The nonhuman primates have parallel neuronal development, similar physiology and complex behaviors similar to humans, making them the most relatable to humans. Cost and ethical concerns can make their use prohibitive.

In preclinical investigations regarding neurological effects of exposure to general anesthesia, rodents were observed to have problems with memory, attention, increased fear and anxiety. Changes noted in synapses, connectivity and genetic material seemed to persist, with the latter being concerning for transmission to offspring. Findings of brain cell death and derangement in behavior following anesthesia exposure were subsequently replicated in primates. The cellular/molecular pathophysiology is unknown, and this knowledge void and limitations of models used in preclinical research have made the translation of findings to humans even more challenging.

Drs. Sun and McCann followed up with a review of the findings of research studies performed at the clinical level. Multiple studies involving large patient databases have shown conflicting and inconclusive outcomes. In studies with concerning outcomes, there was an increased adjusted relative risk of learning disabilities, particularly in language and cognition. This was not replicated in sibling-matched studies and results in twin studies were conflicting. Exposure to greater than two anesthetics seemed to be associated with an increase in the incidence of learning disabilities. Surprisingly, population-based studies out of Canada indicated age 2-4 years as more vulnerable to these adverse events compared to neonates.

Dr. Sun gave an overview of the Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study (sibling matched study in patients less than 36 months), Mayo Anesthesia Safety in Kids (MASK) trial (propensity-guided matching for single and multiple exposures in patients less than 36 months), and the General Anesthesia vs. Spinal (GAS) study (effects of regional anesthesia vs general anesthesia on neurodevelopmental outcomes).

The PANDA, MASK, and GAS studies showed no difference in Intelligence Quotient (IQ) scores, and in the GAS trial this was also not affected by number of exposures. Processing speed and fine motor abilities were noted to be modestly decreased in children with multiple exposures to general anesthesia. However, both panelists noted that children requiring multiple surgical procedures were likely to have other comorbidities, spend more time in the hospital, miss more school days and were likely to be different from children with fewer or no exposure(s).

Dr. Sun who was lead author on the PANDA trial publication in JAMA, and her co-panelists, noted that although the results are reassuring, there are many unresolved questions such as the effect of repeated anesthesia exposure, prolonged duration of anesthesia and import of the diathesis-stress model in this. Members of the audience raised questions about the impact of an enriched environment in the postoperative period, the psychological impact of a hospital environment on children and the potential roles for cognitive and behavioral rehabilitation. It was noted that as adults who have developed coping mechanisms can struggle with hospitalizations, it would not be unexpected for children to struggle with adjusting to the disruption of a surgical procedure and hospital admission.

Contributions from the audience included recommendations regarding the use of regional techniques when appropriate and tailoring the anesthesia plan to analgesia in ages where memory function is underdeveloped.

In conclusion, cognitive function deficits that were found in preclinical studies were absent in children. Although modest fine motor processing was observed, this was only noted with multiple exposures and there were no changes in IQ. Thus, the presenters said it is unlikely that cognition changes are a problem. Behavioral changes (based on parental reports) have however been noted, more so with multiple exposures, and this will continue to be explored in future studies.

The entire perioperative experience is relevant to neurodevelopment and brain health. All facets of perioperative care can impact neurodevelopmental outcomes and should be considered in the perioperative plan.

*Coverage from the SmartTots Panel, Anesthesia and Neurotoxicity: A Conundrum for Clinicians during the IARS 2019 Annual Meeting