Filling Knowledge Gaps for Safe Use of Anesthetics and Sedatives in Children

Adaora M. Chima, MBBS, MPH

SmartTots, the brain child of a union between IARS and the US Food and Drug Administration (FDA), is an initiative that aims to address scientific and clinical gaps regarding the safe use of anesthetics and sedatives in children. A panel of clinical and neuroscience investigators took to the podium to share the ground traversed by SmartTots so far and imagine the future of this research during the session, “Update on SmartTots Initiative and Funded Research,” on Sunday, April 16 at the IARS 2023 Annual Meeting.

Moderator Dean Andropoulos, MD, MHCM, Professor of Anesthesiology and Pediatrics and Vice Chair of Anesthesiology at Baylor College of Medicine, Anesthesiologist-in-Chief and Chair of Anesthesiology at Texas Children’s Hospital, set the stage for the session and introduced the panelists. Uniquely positioned for this discussion, Dr. Andropoulos also serves as the Medical Officer of SmartTots.

Santhanam Suresh, MD, MBA, long-time champion and Steering Committee Chair of SmartTots and IARS Board Chair, reviewed the timeline of SmartTots beginning with its conception in 2009. Serving as Senior Vice-President and Chief of Provider Integration; Arthur C. King Board Designated Professorship in Anesthesiology at Ann & Robert Lurie Children’s Hospital of Chicago and Professor of Anesthesiology and Pediatrics at Northwestern University Feinberg School of Medicine, Dr. Suresh explained that this public-private partnership between the FDA and IARS was entered following concerns raised in 2007 about neurocognitive effects of anesthesia exposure in infancy and childhood. FDA funding for SmartTots spanned 2011-2022 and was wholly dedicated to research initiatives. Although this funding pipeline has come to an end, Dr. Suresh iterated that the IARS is resolute in its continued commitment to supporting SmartTots research projects.

The next panelist Jimcy Platholi, MS, PhD, Assistant Professor of Neuroscience in Anesthesiology at Weill Cornell Medical College, is a 2022 SmartTots Research Grant recipient for her investigation on “Role of Mossy Fiber Terminals in Early Anesthesia Neurotoxicity.” She shared exciting early results from her investigation of the role of mossy fiber terminals in early anesthesia neurotoxicity. Mossy fibers predominantly release glutamate, but are known to release both glutamate and GABA in the immature brain and in the presence of injury. This presents an opportunity for examining anesthetic neurocognitive effects in the age group of concern.

Another element of interest is brain derived neurotrophic factor (BDNF) which also mediates glutamate and GABA neurotransmission and is reduced with exposure to isoflurane. It is deficient in 30% of the human population. This has epidemiological relevance to an investigation that Dr. Platholi is performing to determine if general anesthetics differentially inhibit GABA release from immature mossy fiber terminals which have been altered by a common BDNF polymorphism. Results of very early work showed that amongst three different genotypes that were tested, there was no difference in genetic variation but age showed a definite effect on GABA release, with more inhibition shown in younger cells. Significant inhibition was also demonstrated under isoflurane. Dr. Platholi hopes to further examine the impact of GABA expression on anesthetic sensitivity, reversibility of inhibitory patterns and the relationship with BDNF, amongst other questions.

The third panelist Peter Szmuk, MD, Professor of Anesthesiology and Pain Management at University of Texas Southwestern Medical Center, and Director of Pediatric Clinical Research in the Division of Pediatric Anesthesia at Children’s Medical Center, was one of the investigators on the GAS study in 2019 and is a 2022 SmartTots Research Grant recipient for his current investigation on “Neurodevelopmental Outcome after Standard Dose Sevoflurane versus Low-dose.”

He commenced with a chronological overview of the clinical studies on neurocognitive effects of anesthesia on the developing brain, what is known thus far and provided details of an exciting ongoing multicenter clinical trial, TREX (Toxicity trial of remifentanil and dexmedetomidine).

The TREX study builds upon knowledge gained from the MASK, GAS, and PANDA trials, which had shown that anesthesia exposure of short duration does not have significant neurocognitive effects, regardless of regional or general anesthesia technique.

Alpha-2 agonists and opiates are exempt from the FDA warning regarding neuroapoptosis in the developing brain following exposure to anesthetic agents. This is likely due to their avoidance of NMDA receptor antagonism, with decreased effect of neuroapoptosis. An early rendition of the TREX trial proposed remifentanil and dexmedetomidine combinations with a caudal for surgical anesthesia. Although results were promising, it was impractical for a large-scale study as most surgeries are not amenable to a caudal or the two-hour duration criteria and would be excluded.

Following modifications, the TREX trial is currently underway with 19 international collaborating sites, 7 in Italy, 7 in Australia and 5 in the US. The aim of the trial is to see if a new combination of anesthetic drugs results in a better long-term developmental outcome than the current standard of care for children receiving anesthesia for 2 or more hours.

Children are randomized to receive either a low dose sevoflurane/remifentanil/dexmedetomidine or standard dose sevoflurane anesthetic. Recruitment is almost complete and results are expected to be available in 2026. Thus far, there have been no safety events reported and the incidence of hemodynamic changes has been minimal. Constraints to advancement at the US sites have included the COVID-19 pandemic and funding interruptions, recently rectified by a SmartTots research grant.

This session highlighted critical developments and ongoing work to understand the relationship between anesthesia and the brain. Some progress has been made in investigating the impact of different anesthetic techniques and these findings continue to inform pediatric anesthesia care. It also served as a reminder of the inverse relationship between research funding and progress in anesthesia research. SmartTots remains committed to supporting seminal research in pediatric anesthesia.

If you missed this session, you can still watch session video here.