Searching for Answers to the Unknowns in Pediatric Anesthetic Neurotoxicity Research

The SmartTots panel, “Update on Pediatric Anesthetic Neurotoxicity,” held on May 15 at the IARS 2021 Annual Meeting, addressed timely issues in pediatric anesthesia neurotoxicity research with three dynamic presentations. The presenters Laszlo Vutskits, MD, PhD, Andrew Davidson, MBBS, MD, FANZCA, and Caleb Ing, MD, MS, described priorities in preclinical research and explored challenges in clinical studies and in finding a clinical phenotype in anesthetic neurotoxicity. An update was also provided on the SmartTots-sponsored TREX clinical trial.

SmartTots Medical Officer Dean Andropoulos, MD, MHCM, Professor of Anesthesiology and Pediatrics at Baylor College of Medicine, and Anesthesiologist-In-Chief at Texas Children’s Hospital, moderated the session.

Pre-Clinical Research: What are the priorities?

Laszlo Vutskits, MD, PhD, Head of Pediatric Anesthesia, Department of Anesthesiology, Pharmacology, and Intensive Care at the University Hospital of Geneva, clarified that there are two different kinds of clinical research: basic or fundamental science versus applied or translational science.  The former does not stem from a clinical problem, but 1) aims to describe and understand key experimental phenomena, 2) answers questions that help us understand nature, and 3) organizes answers into theories and models that provide the driving force behind all technological and medical advances. Translational science refers to our ability to take basic science and apply it to real world problems, he asserted.  

The usual flow in research starts with a clinical problem, moves to seeking guidance, and then to laboratory research. In developmental anesthesia neurotoxicity, for the last 20 to 30 years, we have started with lab research, moved to guidance, and then onto the clinical problem, Dr. Vutskits explained. Now, the aim is further understanding the effect of general anesthesia on neural development.  

Translational science should explore the role of surgery and other perioperative factors on brain development. With this approach, there should be real-life relevance, Dr. Vutskits explained. In the perioperative period, there are several parallel factors, including surgery, anesthesia management, and drugs. With surgery, there is an inflammatory cascade that produces neuroinflammation. With anesthesia management, factors such as oxygen and carbon dioxide, sugar, and electrolyte changes occur. With drugs, there are issues in neurotransmission, neural activity, and/or direct toxicity. All of these contribute to physical/functional lesions of nervous tissue, and all of these factors can interact.

There are many unexplored questions of potential translational relevance: What is the impact of surgery on developmental neurotoxicity? Do anesthetics modify, protect, or worsen the impact of surgery on neurodevelopment? How do other perioperative factors influence neurodevelopment? How do the effects of anesthetics combine with the effects of other perioperative factors?

Investigators need to overcome difficulties in proper modeling, shifting from small to bigger animal models. Morbidity and mortality in newborn rodents is high, even in the absence of surgery. There is a need for bigger animals, piglets and nonhuman primates, Dr. Vutskits outlined. 

Raising standards in experimental planning and data reporting is critical. He detailed how incomplete technical and data reporting appears in many scientific publications, rendering these works of limited value as instruments that inform policy or clinical and scientific practice.

Fundamental research on general anesthesia and brain development may need a frame shift in the absence of a convincing human phenotype, Dr. Vutskits explained.

Challenges with Clinical Studies and Update on the T-REX Trial

Picking up where Dr. Vutskits left off, Andrew Davidson, MBBS, MD, FANZCA, continued the discussion on pediatric anesthetic neurotoxicity research. Dr. Davidson is Senior Staff Anaesthetist, Royal Children’s Hospital and Associate Professor, Department of Pediatrics, University of Melbourne; and Director of Clinical Research at the Royal Children’s Hospital, Melbourne.

What are the challenges of clinical studies? We cannot prove that anesthesia is never toxic, Dr. Davidson explained. The best clinical practice is always a synthesis of evidence of varying quality, certainty, and relevance. Studies will always have uncertainty in estimates and variation in population, exposures, and outcomes, he clarified.

It is biologically plausible that anesthesia exposure may have a lasting impact on neurodevelopmental outcomes, as well as other perioperative factors. Many observational studies in children have found evidence for association between anesthesia exposure and neurodevelopmental outcomes, he mentioned. Finding and clarifying other biologically plausible explanations for problems, like pain and hypertension, is the challenge.

Study variation possibilities are many, including multiple exposure types (e.g., short or long, multiple or single), different anesthetics, different ages of exposure, and different patient groups.  There are also many possible outcomes in behavior, cognition, memory, executive function, motor skills, learning, and specific disabilities, like attention deficit hyper-activity disorder (ADHD), Dr. Davidson offered. 

There are many combinations of exposures and outcomes with significant risk of Type 1 error that may only be found by chance. To mitigate this risk, studies require very large numbers and then must be replicated, Dr. Davidson asserted. 

All observational studies are subject to bias and confounding. Adjusting controlling and matching reduces confounding, but never eliminates it. Confounding factors include inflammation, hypotension, stress, pain, and hospitalization. 

What sort of trials should we do? Dr. Davidson suggested large trials or trials on more specific, smaller segments where there is the greatest observational evidence and biological plausibility in a population that has received the most anesthetics or with outcomes that matter most to families and societies. He asserted the need for reliable surrogate outcomes, like biomarkers. Unfortunately, there currently are none.

Update on the T-REX Trial

Dr. Davidson is closely involved with the SmartTots-sponsored T-REX clinical trial, a multinational, multidisciplinary consortium of research centers and hospitals with dozens of collaborators. The name suggests a “killer” trial. Originally, the investigators set out to prove that anesthesia is safe in children by comparing toxic to nontoxic anesthesia with a comprehensive follow-up.  However, this turned out to be unrealistic and they later shifted their focus to whether a plausibly superior treatment has a better outcome, Dr. Davison relayed.

There were limits to the rationale: no observational evidence linking long exposure to any specific neurodevelopmental domain and mixed evidence that dexmedetomidine is nontoxic, Dr. Davidson recalled. Nevertheless, the T-REX trial has proceeded with 450 children under the age of 2 years, receiving more than 2 hours of general anesthesia. One group will receive sevoflurane and another will receive sevoflurane and remifentanil, with follow-up at age 3 years.  Dr. Davidson explained that progress is being made with 190 in each group for a 90% power to detect a 5 point difference. Trial follow-up is underway and doing well with plans to finish recruitment in 2022 with final results in 2025.

What has gone well with the T-REX trial? The protocol is easy to follow, the trial is gaining momentum, and there is strong collaboration among participating groups. Unfortunately, there are not many suitable children with long anesthesia exposure, the neurotoxicity funding environment is exhausted, and COVID-19 has made recruitment more difficult.

Clinical Anesthesia Neurotoxicity: Is there a phenotype?

Caleb Ing, MD, MS, Associate Professor of Anesthesiology (in Epidemiology), Columbia University College of Physicians and Surgeons, followed Dr. Davidson, analyzing more intricacies of pediatric anesthetic neurotoxicity research. He commented on the strength of current literature on anesthetic neurotoxicity. Most studies to date are heterogeneous in many key variables. Therefore, it is not surprising that there is variability, and the majority of studies use preexisting data, he explained.

However, there are benefits to using preexisting data, such as a larger sample size. In anesthetic neurotoxicity, the larger sample sizes are needed to evaluate smaller effects, he added. The limitations of using preexisting data are the potentially suboptimal or unavailable outcomes in the dataset. In addition, they can lack baseline clinical covariates and there can be residual confounding. Clearly, there may be other factors driving problems besides anesthesia, but scientists cannot account for them without the necessary data.

Meta-analysis can help to clarify outcomes. To illustrate, he discussed his study, “Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis,” published in the British Journal of Anaesthesia, which compares findings from the MASK, PANDA, and GAS clinical trials. This meta-analysis excluded all studies of children with a major chronic condition, had tighter inclusion criteria, only included children with a single exposure, only included studies with prospective outcome assessment, and studies with assessment of school-age children who are more than 5 years of age. Dr. Ing’s study evaluated all primary and secondary outcomes and used preexisting data from studies with IQ as the primary outcome, as is the case with GAS, PANDA, and MASK studies.

The findings from Dr. Ing’s meta-analysis of the GAS, PANDA, and MASK studies showed no difference in IQ scores with a single exposure to general anesthesia. The results are very similar for all three trials.  When looking at total behavioral problems, externalizing behavioral problems, and internalizing problems, there are higher and worse behavioral scores after a single exposure by 2 points. However, the size of the association is similar in all three trials. For executive function, children with a single exposure have higher and worse scores by 2.6 points, but this is not statistically significant after multiple comparison adjustments.

In summary, Dr. Ing stated that there is a lot of heterogeneity in the three clinical studies and this makes it difficult to interpret and find a phenotype. A single anesthetic exposure may only be associated with deficits in certain domains. There are no differences in IQ, but behavioral differences appear. Many other studies also report little to no difference in academic achievement, while some studies report higher rates of ADHD.

Dr. Ing concluded that there may be a phenotype but there is not enough evidence to change clinical management; there may be unintended consequences and causality is not established. There is enough evidence to continue to explore the question of whether anesthesia causes deficits in specific domains, such as behavior.