International Anesthesia Research Society
Tje Daily Dose April 2023
An Interview with 2022 SmartTots Research Grant Recipient – Dr. Peter Szmuk
Neurodevelopmental outcome after standard dose sevoflurane versus low-dose
Panel: Update on SmartTots Initiative and Funded Research, Sunday, April 16, 2023, 2:00 pm – 3:00 pm MT, Centennial E-H, The Hyatt Regency Denver at Colorado Convention Center
Early in 2006, Peter Szmuk, MD, first read about the possible effects of anesthetics on the developing brain in infants and young children and was immediately intrigued. He wondered how it was possible that anesthetics could have such life-changing and prolonged effects and yet no one up to that time had noticed it. As the topic became more prominent in the news and in the specialty of pediatric anesthesia due to the GAS study, Dr. Szmuk, now a Clinical Professor in Anesthesiology & Pain Management at UT Southwestern Medical Center, was convinced he needed to contribute to the efforts to uncover answers to this mystery and reached out to join the US arm of the GAS study as the principal investigator at his institution. The findings from that initial study led to his further investigation into this area and participation in the current research study, Phase lll of the TREX trial. This research was also recognized with a 2022 SmartTots Research Award. Dr. Szmuk will share some of the initial results and how these will advance the knowledge around pediatric anesthetic neurotoxicity at the Update on SmartTots Initiative and Funded Research Panel, on Sunday, April 16, during the IARS 2023 Annual Meeting.
1. What drew you to this area of research?
Early in 2006, I first read about the possible effects of anesthetics on the developing brain in infants and young children. The subject intrigued me: How is it possible that anesthetics could have such life-changing and prolonged effects and yet no one up to that time had noticed it? This question quickly became one of the main controversial issues in pediatric anesthesia. With these questions in mind, I contacted Dr. Mary Ellen McCann at Boston Children’s Hospital, who was setting up the US arm of the GAS study. I was delighted to be invited to be involved as our center’s principal investigator.
2. What is the goal of your research?
There are significant differences between basic science and clinical studies conducted in this area of research. While most animal studies including those in nonhuman primates suggest that exposure to general anesthetics at an early age can have a profound effect on brain development, the clinical studies on human subjects were not conclusive. In fact, the main conclusion of the three major clinical trials (the GAS, PANDA and MASK) is that a single, short anesthetic is not neurotoxic.
The current study, the TREX trial, is a phase III, randomized active controlled, parallel group, assessor-blinded, multicenter, international trial comparing the neurodevelopmental outcomes after standard-dose sevoflurane versus the combination of anesthetic drugs (low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia) in young children having anesthesia for 2 hours or longer. A total of 440 infants will be randomized to standard-dose sevoflurane or low-dose sevoflurane/dexmedetomidine/remifentanil-based anesthesia.
The primary endpoint will be the composite cognitive score of the Wechsler Preschool and Primary School Intelligence Scale at 3 years of age. Secondary endpoints will include a battery of other neurocognitive tests evaluating outcomes in general cognitive functioning, language, executive function, memory, adaptive behavior, clinical behavior, and social skills. Additionally, the incidence of the frequency of episodes of light anesthesia, significant intraoperative hypertension, hypotension or bradycardia, postoperative pain, total anesthesia, and recovery time will be examined.
3. What is the potential impact of your research on the field of pediatric anesthesia?
The results from this trial will provide the strongest evidence to date on the effect of over 2 hours or longer anesthesia exposure on the developing brain and an alternative, possibly nonneurotoxic anesthetic regimen for this age group.
4. How do you feel about receiving the IARS SmartTots Award?
My colleagues and I are very thankful to IARS for this SmartTots award. The grant money will be shared by 5 institutions: UT Southwestern and Children’s Health Medical Center, Dallas, TX; Boston Children’s Hospital, Boston, MA; The Children’s Hospital of Philadelphia, Philadelphia, PA; Texas Children’s Hospital, Houston, TX and Cleveland Clinic, Cleveland, OH.
5. How will this award affect your research/professional trajectory?
This multicenter, international trial started more than 5 years ago. While the Australian and Italian centers were able to secure grant support from their national institutions, the US centers have been using local, departmental resources to finance the trial. This grant will significantly help the 5 US centers to increase the rate of enrollment, provide necessary funds for the neuropsychological assessments, and conclude the study sooner.
6. Is there anyone else you wish to acknowledge as part of this research team?
First, I would like to acknowledge the pivotal role of Dr. Andrew Davidson from Murdoch Children’s Research Institute, in Melbourne, AU, for initiating, designing, and leading this international multicenter research group and to Suzette Sheppard, Research Coordinator from the same institution, who is the engine of this trial and is keeping everyone on task.
Second, I would like to acknowledge the hard work of my colleagues Rita Saynhalath, MD, Proshad Efune, MD, Umar Khan, DO, Aveline Jerome, MD, Gigo Alex, MD, Katie Liu, MD, Allisa Doll, MD, and our research coordinators Christina Howard, Kiley Poppino and Marco Fiero who made our center become one of the highest enrollment centers. I also want to thank Lana Harder, MD, and Ana Hernandez, MS, for their hard work with the neuropsychological assessment, especially during the COVID period.
I am grateful to Children’s Health System of Texas for generously supporting part of the cost of the neuropsychological assessment.
Finally, I want to acknowledge my grant co-recipients from the other four US centers: Ann Siu-Lon Ng, MD, from Texas Children’s Hospital, Houston, TX; Pilar Castro, MD, from Cleveland Clinic, Cleveland, OH, Christopher Ward, MD, from The Children’s Hospital of Philadelphia, Philadelphia, PA, and Mary Ellen McCann, MD, from Boston Children’s Hospital, Boston, MA for their contributions in moving this trial forward.
7. What is your vision for the future of this particular area of research?
As I mentioned before, no association with broad measures of intelligence have been identified in clinical studies, but deficits in specific outcomes including behavioral function have been consistently reported and reflect findings from studies of nonhuman primates.
Identifying suitable biomarkers like brain imaging studies and serum-based assays, associated with injury could be extremely valuable in serving as intermediate outcomes that could facilitate clinical studies, and providing insight into potential mechanisms of injury. If a biomarker is found to be associated with long-term outcomes, injury could be identified at an earlier stage, reducing the time between exposure and assessment, and thus reducing the need for lengthy follow-up in clinical studies.
While these results may help identify a phenotype of injury after anesthesia exposure, new approaches to research will still be needed to determine whether a recognized phenotype is caused by the anesthetic medications or other factors related to surgery or the perioperative experience.