Moderated by SmartTots Medical Officer, Dean Andropoulos, MD
Pre-Clinical Research: What are the priorities? Laszlo Vutskits, MD, PhD
Challenges with Clinical Studies and Update on the T-REX Trial -Andrew Davidson, MBBS, MD, FANZCA
Clinical Anesthetic Neurotoxicity: Is there a phenotype? – Caleb Ing, MD, MS

The 2021 SmartTots Panel, held virtually on May 15, addresses timely issues in pediatric anesthesia neurotoxicity research with three dynamic presentations. Dr. Laszlo Vutskits1 discusses priorities in pre-clinical research, Dr. Andrew Davidson2 describes challenges in clinical studies with an update on the SmartTots-sponsored TREX clinical trial, and Dr. Caleb Ing3 explores the challenges of finding a clinical phenotype in anesthetic neurotoxicity. Dr. Dean Andropoulos4 moderates the program with a brief, live question and answer period at the end.

Pre-Clinical Research: What are the priorities?

Laszlo Vutskits, MD, PhD

Clinical research: basic or fundamental science vs. applied or translational science

Dr. Vutskits clarifies 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—“it should be dictated by an identified real clinical problem,” he asserts.

The usual flow in research starts from a clinical problem and goes to 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.

Basic science: do we need more?

Do we need more basic science on developmental anesthesia neurotoxicity?” asks Dr. Vutskits. One answer is “no, there is ample fundamental evidence that general anesthesia can affect brain development,” he adds. The answer can also be “yes, extending fundamental knowledge may fuel further translational and clinical research. General anesthesia is a powerful model for studying the impact of neuronal activity on brain development…we need to reframe the goals to make it relevant. It may be better to say that we want to further understand the effect of general anesthesia on neural development.”

Translational approach: unexplored questions

What is a translational approach? “There should be real-life relevance,” injects Dr. Vutskits.

Is the perioperative period dangerous for brain? He suggests we look at 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 O2 and CO2, 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 with each other.

There are many unexplored questions of potential translational relevance: What is the impact of surgery on developmental neurotoxicty? 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?

Reductionist or holistic approach?

“There is room for a holistic approach,” comments Dr. Vutskits. However, most biomedical science in the 20th century uses the reductionist approach. “It’s useful with important limitations,” he offers. Reductionist and holistic approaches are interdependent and complimentary. “They help make sense of complex phenomena, but there is a need for more holistic approaches.” This is due to all of the factors in the surgery-anesthesia management-drugs translational approach, given the way they interact or do not interact, or combine with each other, or act alone.

Technical challenges in lab science

There is a size issue. Morbidity and mortality in newborn rodents is high, even in the absence of surgery. There is a need for bigger animals, piglets and non-human primates. “A majority of lab science is under powered,” observes Dr. Vutskits.

There is a quality and reporting issue. Raising standards in experimental planning and data reporting is critical. “We see this in incomplete technical and data reporting in many scientific publications, rendering these works of limited value as instruments that inform policy or clinical and scientific practice,” he laments.

In closing, Dr. Vutskits shares this quote from Eckhart Tolle: “When you become comfortable with uncertainty, infinite possibilities open up your life.”

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

Andrew Davidson, MBBS, MD, FANZCA

“Long ago, my father warned me that I could not disprove the existence of dragons,” recalls Dr. Davidson as he opens his presentation. “It is difficult to prove non-existence in anesthesia-induced neurotoxicity and you’ll have trouble finding it with an infinite number of experiments,” he adds.

Proving anesthetic neurotoxicity

What are the challenges of clinical studies? We cannot prove that anesthesia is never toxic. “The best clinical practice is always a synthesis of evidence of varying quality, certainty, and relevance. There will always be uncertainty around estimate, always variation in population, exposures, and outcomes,” he clarifies.

Finding a clinical framework: many questions

What is the logical framework for clinical studies? Is there biological plausibility? Is there any observed association? What exposure is associated with what outcomes? Can we identify possible causal relationships? What are the plausible bases for trials? Do interventions improve the outcome in trials? These are key questions.

It is biologically plausible that anesthesia exposure may have a lasting impact on neurodevelopmental outcomes. “There is ample evidence,” answers Davidson. It is also biologically plausible that other perioperative factors may have an impact. “Yes, numerous studies have found evidence for association—observational studies, in children.”

One challenge is multiple exposure types, including short or long, multiple or single, the different anesthetics, different ages of exposure, and different patient groups. What is associated with what?

“There are many possible outcomes in behavior, cognition, memory, executive function, motor skills, learning, and there are specific disabilities, like ADHD,” offers Davidson. Where do we look first? What is biologically most likely from pre-clinical studies? Do we look for what actually matters most to families and society?

“There are many combinations of exposures and outcomes with significant risk of Type 1 error—that we find something by chance. To mitigate this risk, we need very large numbers and the studies must be replicated,” asserts Davidson. “To identify possible causal relationships in clinical studies, we need replication and similarities across studies, a biological gradient, strong associations with a large effect size, the ability to minimize confounding factors and experimental, randomized trials,” he emphasizes.

Confounding factors

All observational studies are subject to bias and confounding. Adjusting controlling and matching reduces confounding, but never eliminates it. “The larger the study, the more confounding factors,” admits Dr. Davidson. Confounding factors include inflammation, hypotension, stress, pain, and hospitalization. “It can be difficult to untangle them from the study…randomized trials are the gold standard.”

What are plausible bases for trials? “When there is strong evidence for an association in observational studies and where there is a biological plausibility that the intervention would work in that a specific population,” he states.

Clinical trials and interventions in the future: what to do?

What sort of trials should we do? Dr. Davidson suggests large trials or trials on more specific smaller segments…“where there is the greatest observational evidence and biological plausibility in a population that has the most anesthetics or with outcomes that matter most to families and societies.”

In regard to interventions, “we need to balance biological plausibility of non-toxicity with safety and ease of administration. It’s not immediately obvious which is best.”

Challenges for future clinical trials

Dr. Davidson summarizes the challenges for future clinical trials:

  • Finding large numbers to detect small differences
  • Finding a non-toxic intervention…”it’s not easy because one cannot do surgery without anesthesia.”
  • Timing of the outcome…“we need to wait a long time before injury is apparent. The time between the trial exposure and outcome may be too long.”
  • Mitigating these problems…“we need reliable surrogate outcomes, like biomarkers. Currently there are none.”
  • Finding and clarifying other biologically plausible explanations for problems, like pain and hypertension.
  • 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. Originally, they set out to prove that anesthesia is safe in children. They would compare toxic to non-toxic anesthesia with a comprehensive follow up. “This turned out to be unrealistic,” he comments. “We later shifted to seeing if a plausibly superior treatment has a better outcome.”

    “There were limits to the rationale: no observational evidence linking long exposure to any specific neurodevelopmental domain and mixed evidence that dexmedetomine is non-toxic,” admits Davidson. Nevertheless, T-REX has gone ahead with 450 children under the age of 2 years having more than 2 hours of general anesthesia. Children will be randomized to receive either a low dose sevoflurane/remifentanil/dexmedetomidine or standard dose sevoflurane anesthetic. Follow up is at age 3 years of age. IQ is the primary outcome measure. “We are making progress; there are 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.

    What has not gone well? There are not that many suitable children with long anesthesia exposure, the neurotoxicity funding environment is exhausted, and COVID has added more difficulty to recruitment.

    Final comments

    Dr. Davidson believes there is still a place for large cohort studies to identify the nature of associations. Confounding factors will continue to limit the ability of researchers to find causal relationships. “There’s a place for more carefully designed trials, but they will be long and expensive. It’s time to think beyond neurotoxicity.”

    Clinical Anesthesia Neurotoxicity: Is there a phenotype?

    Caleb Ing, MD, MS

    Current anesthetic neurotoxicity literature

    Dr. Ing starts his presentation with comments on the strength of current literature on anesthetic neurotoxicity. “Many say it’s mixed, but it’s more complicated than that.” Most studies to date are very heterogeneous in many key variables. Therefore, “it’s not surprising that there’s variability, and a vast majority of studies use pre-existing data.”

    Benefits and limitations of pre-existing data

    There are benefits to using pre-existing data. It can be more efficient and offers a larger sample size.
    “In anesthetic neurotoxicity, it can be good because larger sample sizes are needed to evaluate smaller effects,” he adds. The limitations to using pre-existing data relate to outcomes—they must be available in the dataset—and most are potentially sub-optimal. Further, 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 because they are lacking the necessary data.

    Meta-analysis of the PANDA, MASK, and GAS clinical trials

    How do we avoid the limitations of pre-existing data and have larger sample sizes? “Meta-analysis can help,” clarifies Ing. To illustrate, he discusses his study, Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis5, which compares findings from the MASK, PANDA, and GAS clinical trials. This meta-analysis excludes all studies of children with a major chronic condition, has tighter inclusion criteria, only includes children with a single exposure, only includes studies with prospective outcome assessment, and studies with assessment of school age children who are more than 5 years of age. Ing’s study evaluates all primary and secondary outcomes and uses pre-existing data from studies with IQ as the primary outcome, as is the case with GAS, PANDA, and MASK studies.

    The findings from Ing’s meta-analysis of the GAS, PANDA, and MASK studies show 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/worse behavioral scores after a single exposure by 2 points, but the size of the association is similar in all three trials. For executive function, children with a single exposure have higher/worse scores by 2.6 points, but this is not statistically significant after multiple comparison adjustments.

    Results of secondary analysis

    “The tricky thing about scores is to figure out exactly what a 2 point score difference means,” comments Ing. A secondary analysis can help to show if the 2 point different in scores is associated with a clinical deficit. Ing defines a clinical deficit as 1 standard deviation worse than the mean score of the populations—those at 16% of all normalized scores. He found no statistically significant increased risk of total and externalizing behavioral problem. However, he did find a 47% increased risk of an internalizing behavioral deficit and a 68% increased risk of executive function deficit. Why did they use the 1 standard deviations threshold? The reasons are 1) sample size, 2) if the population shifts, the threshold is not likely to matter, and 3) two standard deviations is the high bar.

    Ruling out bias in parental reporting

    Ing highlights his findings with the The Child Behavior Checklist and Behavior Rating Inventory of Executive Function. These include parent and caregiver reporting. Is there bias? With GAS, he did a secondary analysis on parent reporting and found that parental knowledge of general anesthesia does not appear to bias survey outcomes.

    Conclusion about a phenotype

    In summary, Dr. Ing states, “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. Some studies report higher rates of attention deficit hyper-activity disorder, ADHD.

    Finally, is there a phenotype? “Maybe, in my opinion,” concludes Ing. “There is not enough evidence to change clinical management since 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.”

    1. Laszlo Vutskits, MD, PhD, is Head of Pediatric Anesthesia, Department of Anesthesiology, Pharmacology, and Intensive Care at the University Hospital of Geneva; President-Elect of the European Society for Paediatric Anaesthesiology; Editor of Anesthesiology; and Section Editor, Pediatric Anesthesia.
    2. Andrew Davidson, MBBS, MD, FANZCA, 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, Australia.
    3. Caleb Ing is Associate Professor of Anesthesiology (in Epidemiology), Columbia University College of Physicians and Surgeons, New York.
    4. Dean Andropoulos, MD, MHCM, is Professor of Anesthesiology and Pediatrics, Baylor College of Medicine, Houston; and Anesthesiologist-In-Chief, Texas Children’s Hospital, Houston, Texas.
    5. Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis. Ing, Jackson, Zaccariello, Goldberg, McCann, Grobler, Davidon, Sun, Li, & Warner. February 2021.

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