Dr. Ruth Graham - The Hydra of Anesthetic Neurotoxicity

Tomic Kusos here so we can get started. Good, good morning. Uh, welcome to anesthesia and, and General Surgery grand rounds. Um, this morning, we have a special lecture from, uh, a, a really close friend, uh, and, and she'll be addressing an issue that's been really close to our hearts here. Uh, certainly, the issue of uh anesthetic-induced developmental neurotoxicity has been in the minds of both, um, uh, pediatric anesthesiologists and as, as well as all the pediatric caregivers, uh, in the past, uh, few decades. Um, certainly, it's impacted our practice to the point that in the recent, uh, PANDA symposium, uh, that was held in New York City, about 22 weeks ago, um, it's changed the practice of, uh, radiologists and neurologists ordering MRIs as well as some plastic surgeons as well, uh, delaying some cases due to the FDA, um, um, uh, safety concerns about using anesthetics for, uh, infants and children. To address this issue, we have Doctor Ruth Graham from the University of Manitoba. Uh, Ruth Graham is, um, is a well-known, uh, person in, in our, our field. Uh, but more importantly, she spent some time here. Prior to coming over here, she did a research fellowship in, um, respiratory and cardiovascular physiology and did a, uh, uh, anesthesia residency, that was followed by a, a fellowship in pediatric anesthesia here at Children's Hospital. Uh, she was in the class of 1990 and was the chief fellow at that point. She returned to Manitoba and, and, and did a lot of work in, uh, respiratory and pulmonary, uh, cardiovascular physiology, and, uh, subsequently became chief of her department at Winnipeg Children's Hospital. Uh, for, uh, she just finished her, um, her term or her service, let's put it that way, in that, in that area, and it's finally come back to the realm of looking at, uh, pertinent issues in pediatric anesthesia, and more importantly, the issue of Aztec-induced neurotoxicity. She was a recipient of a, a grant, uh, from, um, the Manitoba grant in the council for research looking at this aspect, and she's published one, probably one of the landmark studies and looking at the, the clinical aspects of aesthetic neurotoxicity. Ruth was here with me back when, um, the, the anesthesia officers were down in the Honeywell basement. We had, you know, ICU used to, used to be in Pavilion 5. The cafeteria used to look over the Prouty Garden, uh. And now it's completely transformed. It's been about almost 30 years since she's last visited here. So please welcome, uh, uh, Dr. Ruth Graham, and she'll be talking about the hydra of anesthetic neurotoxicity. Ruth? Well, that was a little overwhelming introduction, so. Um, I have to, I'm just, I'm so grateful to be here, and I'm so excited to be amongst you, but I have to tell you, well, first of all, I have to tell you I have nothing to disclose, but I have to tell you, I actually find this quite daunting to come back to a place where those people were my staff people 28 years ago, and if you'll notice, this is going by itself, so, why is that doing that? A lot of these faces are still very familiar, and in fact, they haven't changed at all. Whereas compared to this motley crew of fellows, my fellow fellows, you might notice a few familiar faces. And they haven't changed much either, compared to what I feel like a train wreck these days. However, I thought we, um, I'm, I'm, and I'm also consider it quite daunting because I really did consider this one of the best parts of this fellowship was this lecture series, and so to be standing on the shoulders of all these superb speakers that came here and spoke to us, it, it really is daunting to be up here again. Anyways, I, I've labeled this talk the hydra of anesthetic neurotoxicity. I don't know if you remember the the myth of Hercules, his second labor was the slaying of the hydra. The hydra was a nine-headed serpentine beast that every time you cut off one head, another grew back too, so it was a never ending problem. So how I can I see the sort of notion of anesthetic neurotoxicity and the hydra is that what was the initial description of widespread so, I have to stop, this is just going all by itself. I don't know how to make this do this. Help! Sorry, that what started out initially as, hey, as a as just generalized neuro apoptosis with the exposure to a significant amount of anesthetic. Has now multiplied into, oops sorry, going the wrong way, has multiplied into abnormalities at virtually every level level of neurogenesis, including glial apoptosis, synapse formation, impaired dendritic spine formation, faulty axonal it's triggering and mitochondrial and sarcoplasmic reticulum damage. And likewise, the initial uh outcome of concerns regarding learning and memory in rats with exposure to a significant amount of anesthetic has now multiplied into impairments at virtually every level of neural uh developmental functioning, including, uh, motor deficits, uh, behavioral abnormalities, anxiety disorders, impaired motivation, learning disabilities, changes in school performance and IQ. Uh, why you just keep doing this, um, so to me that that that we're we're sitting here with, uh, despite what is now almost 20 years of, uh, it's just scrolling. How do I get it? Thanks. I speak fast enough as it is. Hopefully do it for you here. No, captain. No, it's uh, can I just come in? Yeah, let's just double check. OK, that's how it was supposed to go, but I need to move way far ahead. Make sure it doesn't go by itself. OK, no, it's good. I think, I think we're good. Thanks so much, Chris. OK, sorry about that guys. So, despite what is now over 15 years of intense uh study, both in the pre-clinical and the clinical realm, we are still struck with many heads of unanswered questions, including if there is a window of vulnerability in children the way it's been demonstrated in, uh, animals. Is there a significant dose and duration of exposure that we need to worry about? And what developmental, uh, domain is there of concern? Are we looking at behavior? Are we looking at intellectual function? Are we looking at anxiety? Despite uh This, uh, relative unanswered questions. The FDA, I'm sure everybody in this room is familiar with the FDA statement that came out at the end of, uh, uh 2016, suggesting that, um, that that repeated or lengthy use of general anesthesia and and sedative drugs in procedures in children less than 3 may affect the development of children's brains and suggest that procedures that may last longer than 3 hours. Or, uh, that, that we need to balance the benefits of anesthesia in young children against the potential risks, especially for procedures that are over 3 hours of age. If we need multiple procedures and in children less than 3. So, what I'd like to just review today in this rather huge topic is just review very briefly the basis of the FDA warning. I'd like to present the more recent clinical findings, the, the studies that have been published since the advent of the FDA warning that actually sort of present some concerns about the, the, the, uh, information that they present. And this and to bring together the challenges that go into translating pre-clinical findings to the clinical realm and offer what might be some potential approaches to future work to help try and move this forward. What is the basis of the FDA warning? By and large, this is largely based on animal studies on pre-clinical um findings in animals anywhere from rats to non-human primates. But virtually the majority of those studies show that given a sufficient dose and duration of anesthetic, but it has to be a sufficient dose and duration. In a specific period of vulnerability in this first study by Jeff Tovic and Trodorovic. Um, using rats, that translated to this is day 7, postnatal age, which is the period of peak neurogenesesis in the rat, is associated with, in this study, widespread neuroapoptosis and later, uh, neurocognitive deficits. But what you need is a specific dose, a specific, uh, time period to, in order to manifest abnormalities. The other studies that have gone on, and there are hundreds of them now, uh, looking at either, uh, this is another rat study by Zawa Al more recently, also say that there, the importance in preclinical studies is that there's a dose dependent structural abnormality. So this in this in this study, they were looking at dendritic spine abnormalities at with 1 hour versus 6 hours of seva fluing, that there's a dose dependent structural abnormality, there's a dose dependent functional abnormality, this, in this case, looking at long term hippocampal potentiation. And there's a dose dependent effect on neurocognitive function, meaning you needed 6 hours of sevoflurane anesthesia in the rat model in order to demonstrate abnormalities in learning and memory. Um, so that, that, that, but those are the largely based animal studies that would that formed the basis of the FDA warning. That was in combination at the time. Of the two large, uh, single anesthetic exposure studies that, that were initiated by CERN, so the gas and the PANDA trial. I wasn't going to spend a whole lot of time on each of these cause I think we're all pretty aware of these studies. The GAS trial was the first and only to this date randomized control trial comparing regional anesthesia to general anesthesia in infants having hernia repair, and the PANDA trial, which was an Ambidirectional trial, taking a retrospective cohort of children having hernia repair again, less than 3 years of age compared to their siblings and looking at uh general uh IQs. Which found absolutely no difference between exposed and non-exposed children with a single short anesthetic. Um, So that in combination with a number of the very earliest epidemiological studies, most notably from the Mayo Clinic Group, which showed um in a, in a retrospective population cohort that a single anesthetic exposure was not associated with increases in the incidence of or in in the diagnosis of learning disabilities in the cohort of children. But greater than equal to 2 anesthetics was associated with a two-fold increase in um the incidence of learning disabilities. So that formed the basis of the FDA um warning at the time that it came out. What why age less than 3 years? That was, that was a completely translated concern based on animal studies. This is a complicated looking slide, but it's showing um uh neurodevelopmental uh growth across species, which you can see is very variable, but the most important thing is that time scale is different depending on the species. So whereas this line, which is the rat, Uh, this, the rat timescale is in days. The, uh, rats, uh, brain growth peaks at day 7 to 10 post gestinal age and is finished by about 2 weeks. The monkey actually has most of his neural, his neural growth happening prenatally. This is over a period of weeks, and so the monkey, uh, brain growth peaks prenatally and is virtually finished within the first couple of weeks post birth, and you can see that monkeys are born much more developed than humans are for sure. Whereas this, this is the man, um, neural growth, which, and this time scale is over months, so that, uh, the the peak period of neural neurogenesis and brain growth happens. Perinatally, sort of in the last trimester of pregnancy, probably up to the 1st 11 to 2 years of life. And although brain growth continues to 3 or 4 years, the synaptogenesis and brain growth continues. It in fact also continues all the way to young adulthood, you know, there's another peak of brain growth in adolescence that hasn't even been considered in this literature. So we're looking at very different time scales of neural development and very different complexity. But however, that's, they looked at age less than 3 years based on the time course of maximal brain growth. So, what is the clinical, is there clinical evidence for increased risk with exposure in kids less than 3 years of age? Um, I'd like to now sort of focus on the more recent, much larger, better controlled, uh, retrospective cohort studies that have been published very shortly after the FDA warning came out. Two of them from Canada, thank you very much. Um, Including, uh, that, that were done quite independently and one the the largest retrospective matched cohort study which was from Sweden. Um, all of these came out within six months of each other. This first study is from Ontario. This is the study that we conducted in Manitoba, and this is the Swedish study. You look at the combined kids exposed in these three studies is about 60,000 kids, 30,000 of them less than 2 years of age. So these are significantly larger than any of the previous epidemiological studies done to date. And the overall, and so I'm sorry, I have to go back a little bit. Both uh the Ontario and the Manitoba study are, uh, actually looked at quite independently, came up, that we have a large, the advantage of living in a, in a single-payer, uh, health system is that we have large population-based databases in most provinces that combine health, educational, and socioeconomic and socio-demographic data for the entire population. So that in in this way, we were able to do linked studies looking at in the outcome in both of these provincial studies was looking at an instrument called the Early Development Instrument, which is a which is a test of school readiness that's conducted that's given to every child in public school at in in kindergarten. And it's been well validated as a predictor of future school performance. Um, whereas the, so, and we looked at, um, children exposed to anesthesia before age 4 compared to matched to 2 to 3 times the number of children not exposed, with lots of control for socio-demographics, health status, and uh birth characteristics. The, the Swedish study looked at, um, Uh, a population-based study, 33,000 kids exposed to anesthetics less than age 4, compared to an unexposed cohort from that population, and looked at school school performance in a country where they have standardized testing at age 16 with a standardized curriculum across the country. And looked at IQ at the at um At an army entrance at age 18 and boys. Um, the overall results of each of these three studies was actually quite similar, although each of them did find small increases in vulnerability or in abnormalities with those measures that were indicated, they were exceedingly small compared to the Uh, differences that were seen in earlier studies. So in the O'Leary Group that was from Ontario, they looked at, uh, vulnerability from the early development instrument that was looking at kids who scored in the lowest 10th percentile and found that Although there was a difference, the, the, the difference between the exposed and the unexposed kids in the incidence of vulnerability was 0.6%. 25.6% of kids exposed to anesthesia scored in the lowest 10th percentile versus 25%. That was significant because the numbers were so high, but with an adjusted odds ratio of 1.05, but that's an extremely small um uh effect size. Likewise, in the Swedish study looking at school grades at age 16, um, the exposed group had scores that were less than 1% lower than the unexposed group. And the same held true with the IQ testing at military entrance. In our study, uh, we, instead of looking at vulnerability from the EDI testing, we looked at the scores that the kids got in each of the five domains and found that exposed test scores in selected domains were between 0.3 and 0.7 points lower than the unexposed X-rays uh than the unexposed kids, suggesting again an extremely small effect size. But significant. However, each of us, each of these studies also looked at the association of, of, um, those effect sizes by age. In the O'Leary group, In the Ontario study, they compared kids less than 2 versus kids greater than 2, and found absolutely no difference in the um EDI vulnerability, that's the odds ratio for kids under 2 is actually not even significant. Uh, with an odds ratio of 1.04, again, extremely small. In the Swedish study. Um, with 33,000 kids exposed, looking at school grades at age 16, in fact, only the kids older than 3 had significant, uh, had a significant, uh, decrease in their school grades. And in fact, the differences in their overall group was entirely accounted for by the older kids in the cohort, not by the kids less than 3. And the same holds true in our study. This was, this is looking at the, uh, the estimates for scores across each of the five domains in the EDI testing. By age, so the, the red bars is the 0 to 2 year olds, this is 2 to 3 and 3 to 4 year olds, and in fact, um, there was absolutely no association between uh test score results and age less than 2 in this population, that our results were entirely accounted for, again, by the older kids in the cohort. So if you look at the combined results from these three large population studies, now looking at 30,000 kids less than 2 years of age. We can't really find evidence for a greater adverse association with neuro with anesthetic exposure and neurodevelopment in the kids that you would assume to be at the greatest risk, the kids less than 2. Likewise, so Caleb Bingedda has also gone back. And to to do an observational cohort study looking at Medicaid claims using combined Texas and New York data. They looked at a single anesthetic exposure in kids under 5, having either just one of 4 procedures, pyloromyotomy, inguinal hernia, circumcision, or TNAs. They looked at 38,000 kids. So now we're looking at, as again, much larger population of children who were propensity matched to more than almost 200,000 kids unexposed. They looked they looked at different outcomes, so they're looking at specifically uh a diagnosis of developmental delay, ADHD or any mental disorder that was diagnosed by ICD-9 codes in this large Medicaid cohort. And and showed that overall, as uh they too showed very small but significant increase overall in each of those diagnoses subsequent to anesthetic exposure in this Medicaid cohort. But this is, this is showing the age range for uh by 6 months for each of those um results, and absolutely no difference between the youngest children and the oldest children, even up to 5 years of age. So they had a, a combined hazards ratio of about 1.26 in each of those domains, but not different by age. So, looking at this, these studies together, we don't really have a very strong evidence in the more recent cohorts of an age effect that of a concern for anesthetic neurotoxicity associated in children less than 3 years of age. You can sort of question this. So does that mean that there's a, there's a, there's no age above which risk decreases with anesthetic exposure? Because we do know that uh uh uh neural growth and, and, uh, regional differences in brain growth. can account for differences by age. There is some suggestion that it's the the age of the neuron that's more important than the age of the child, and so with different periods growing at different stages, maybe we're looking at different outcomes based on the age of the neuron that's being exposed. However, um, in order to account for the lack of effect in the youngest children, you might also have to postulate that there's repair and neuroplasticity to account for the less effect in kids who are the youngest being exposed. It it also raises the possibility that this vulnerable here that's been so well documented in animals just doesn't exist in humans. So, then, is there clinical evidence for increased risk with increased length or of exposure or for multiple exposures uh in the more recent um studies? I'm gonna go back to these same three retrospective cohort studies. Cause they looked at this as well. Um, so in the Ontario group, uh, they, they separated the, uh, the results by number of, uh, surgeries, 123, or greater than 4, and found they could find no difference in the odds ratio for increased vulnerability from 1 anesthetic exposure to greater than 4 anesthetic exposures. The odds ratio stayed at 1.06. This is with huge numbers of kids in these studies compared to the previous epidemiological studies. The first study done, for example, by Wilder Adel, the kids with multiple exposures was 100. This is the, the, this multiple exposure is 5000. So we're looking at a much greater power in, in, in terms, in terms of being able to understand the results. Likewise, in the Swedish study, Gla did show that there was a moderate increase in in the risk for uh decreasing school grades with greater than 3 exposures. However, the, you can see that the the confidence intervals around these numbers gets huge with increasing exposures, so that it's no longer significant because of overlapping confidence intervals. Um, likewise, in our study where, uh, we compared single versus multiple anesthetic exposures for the entire group, um, the, the small differences seen, yeah, yeah, this is a very blown up slide, I have to tell you over every domain. This is looking at a difference in 0.5 scores out of 10. So, uh, but nonetheless, the difference, that, that, that small difference we saw across most domains. With a single anesthetic exposure was no different with multiple anesthetic exposures, that the confidence intervals also completely overlap. So those 3 large cohort studies don't provide a great deal of evidence that there's a dose response with anesthetic exposure in the, in the outcomes that they were, were looking at. This is in stark contrast with the Mayo Clinic Group, which has, this is the first study I showed you already. We've, I think we've seen this slide in virtually every presentation of anesthetic neurotoxicity. However, they repeated that study because of the concerns about um confounding and small numbers, uh, but, and, and that, that it was done in a very old cohort with older anesthetic agents and less anesthetic monitoring. So they, they repeated this just in the last year, using a retrospective birth cohort from 1996 to 2000 with more modern anesthetics. And, and this time they propensity matched the kids for sex, birth weight, all the kinds of things that we know are of concern, uh, for neurodevelopmental outcomes, and prospectively looked at learning disabilities or the diagnosis of ADHD. Um, over the next 16 years. Again, these are not huge numbers. This study is a small study, uh, looking at multiple anesthetic exposures in this group, it's again in the hundreds instead of in the thousands. And showed exactly the same thing they showed before. So, as opposed to the other uh uh uh the the other large uh population cohorts, a single anesthetic exposure in this group was not associated with an increased risk for learning disabilities or ADHD, but multiple anesthetic exposures was associated with a twofold increase in hazard ratio for both of those diagnoses. And finally, the long awaited results of the mask trial have has just been published ahead of print. Same group of people, actually. But, but this was, this was the, uh, a study that's been underway for years and years, looking at a propensity matched birth cohort from a more recent birth cohort, looking at no versus 1 versus two general anesthetics with prospective individual neuropsych testing at age 8 to 12 or 150 to 20 years. This just came out this past month. And interesting that their primary outcome was full scale IQ testing at those age ranges, and interestingly, they showed absolutely no difference between single and multiple anesthetic exposures in their full scale IQ testing, um, As a primary outcome. Looking at secondary outcomes, looking at subsets of uh of the, of the uh study characteristics, they did show a a small decrease in processing speed and fine motor abilities in children who had multiple anesthetic exposures, and the parents of kids um who uh with multiple anesthetics reported exposures reported increased concerns about behavior, reading, and executive function. Um One of the trouble with this study and with other studies in which you have to solicit uh parents to provide their children for subsequent testing is that there's a, there's a real risk for a selection bias, and then that the parents who have greater concerns are more likely to have their children come and be tested. So it raises that issue always when you're looking at secondary outcomes, you have to be concerned about other biases that go into the uh outcome. So we're left, so we have those 3 large studies which don't provide very good evidence for a dose response versus the Mayo Clinic Group, which does, except for their primary outcomes with their um with their most recent mass study. The, so the, the, the, these are very difficult studies to all put together and try and glean results that make sense. I Is this because of the outcome selected? So, uh, the three large cohort studies looked at outcomes such as, um, uh, um, school readiness and, and school performance, or behavior and learning disability domains. A different domain than than what we were looking at in our studies. Are they more sensitive? Are we looking at different populations of kids? Are we looking at kids with specific vulnerabilities in the Mayo Group or specific surgical procedures that are overrepresented in one study versus another? Um, the, the Swedish study suggested that there, there was differing vulnerabilities based on surgical procedure. For example, ENT surgery and eye surgery had increased risks of lower school grades than hernia repair, for example. And are, is this really an anesthetic we're looking at the effect we're looking at, these small differences that we see, or is this still all just confounding that we're looking at the vulnerabilities that a child comes to the anesthetic with, is responsible for the anesthetic exposure and responsible for the subsequent um small abnormalities that we're seeing in neurodevelopment. But I think regardless of our lack of clarity about what this means, it does suggest that there's a real problem with translation from the very clear animals work, which has, which repeatedly shows significant abnormalities with specific doses in some specific domains with a specific age range of exposure. And the real difficult, the real trouble with trying to correlate these two pre-clinical studies occur in a very controlled environment in the entire perioperative period. They have a controlled anesthetic exposure, they usually are involved in similar strains and genetics of animals involved in the exposure, and they have no surgery. Whereas in all clinical studies, children come to have anesthetic because for because they have an indication for surgery with a surgical procedure that occurs and exposure to anesthesia occurs within a continuum of the factors that shape neurodevelopment over the entire course of human brain growth and development. Genetic, biologic, psychosocial and environmental factors play a role in brain development. Continually versus a single anesthetic exposure for however many hours in the course of that brain development. But that's, and so the, the, our ability to tease out any anesthetic effect, any putative anesthetic effects in the context of all of these factors that influence neurodevelopment is obviously challenging, but that's the crux of the problem, right? This is that, this is the patients that we're dealing with. And um despite our genetic similarities, the, you know, um, gene expression is obviously different between humans and monkeys, and the complexity of brain development is quite significantly different as well. This is a monkey brain, this is a human brain, so they may be our closest relatives and are the best um pre-clinical tool we have to look at this, we are not the same species. So what are the significance of other factors that are relevant to human brain growth and development? The interesting part about uh uh uh of doing large cohort studies with uh multiple covariates is you can look at the influence of the other covariants on the outcome of interest as well. So, um, Blatz, the Swedish studied this, did this as, as well. And showed that the the very small effect of surgical surgery and anesthesia on school grades was about a tenfold difference in association compared to sex, being born later in the year, and maternal education. And in our study, we showed the very small Uh, association between anesthetic exposure and EDI test scores was at least threefold less than the social determinants of growth and development and health, that being income assistance, that's being involved in the welfare system in the Canadian system, and CFS stands for Child and Family Services. Those are children who at any time had been taken from their families and been uh involved in, in the child welfare system. So other factors are hugely important in the outcomes that we're looking at. But we also know there are, there are environmental, uh, and other factors that have significant effects on, on neurodevelopment, inflammation and stress, even micronutrients and micronutrient deficiencies have profound effects on brain growth and development over the course of, um, the child's growth. There's even information on the gut microbiota and the importance of the normal gut microbiota in terms of immune signaling, microglial growth and development, blood-brain barrier function. The list goes on and on. So, as I say, there this anesthetic exposure occurs in the context of a huge number, a number of factors that have equally important, if not more, effects on brain growth and development. I'm not going to speak about all of those specifically, but um just looking at sustained stress responses in children who were uh raised in deprivation and Romanian orphans raised in deprivation. Um, uh, adverse childhood experiences, chaotic lives are associated with decreased hippocampal, prefrontal and temporal activity here shown by, uh, P PET, uh, imaging. And associated with impairments in learning, memory, and the ability to regulate certain stress responses, all those things that we're looking at with neuro anesthetic toxicity. Likewise, if uh uh this this group looked at Bangladeshi kids raised in poverty and followed them prospectively from birth and looked at CRP as an evidence of inflammatory markers to show that sustained stress and sustained increases in inflammatory markers is associated with decreased neurocognitive assessments. This is at 40 weeks of age across every domain. So going forward, I think we have to move towards looking at general anesthesia exposure within the context of all the perioperative factors that, that go into the growth and development of this child. That we might need to now focus more on specific populations that may be at risk and and perhaps specific procedures. I'd like to just uh propose another group in, at, at my institution has looked at this from the adult side. There's the, the whole concern about postoperative delirium and cognitive dysfunction um is also considered to be potentially a problem associated with general anesthetic, with brains at risk at the opposite end of the developmental spectrum. Um A group at our institution did this is initial uh results from a pilot study looking at older uh adults undergoing major non-cardiac surgery. They, they, their goal was to look at factors that might be associated with the incidence of postoperative delirium, post-op cognitive dysfunction, and so they did very careful and uh extensive preoperative neurocognitive and psychiatric testing. They did preoperative imaging with MRI's and a a preoperative MRICO2 stress test, which I'll explain in a minute. Um, they followed the patients intraoperatively with high fidelity monitoring of, uh, hemodynamics, carbon dioxide, uh, brain oximetry, and followed them postoperatively for delirium for the 1st 5 days and over the first month. Um, and, a, a pre-op MRI stress test was developed by in Toronto and in Manitoba, looking at cerebral blood flow responses to a very controlled small change in CO2, uh, using bold imaging blood oxygen level, uh, dependent imaging by MRI. So they, they've developed a, a, a mass system that allows you to change CO2 in a very stepwise manner with a very small controlled increase in CO2 with no change in inspired oxygen. While, while in the MRI scanner and look at the cerebrovascular uh uh uh response where um increased orange and red suggests increased blood flow, the normal response to a small increase in CO2, but areas of the brain where you have abnormal cerebrovascular reactivity don't light up the same way, suggesting that there are areas of the brain at risk regionally in terms of CO2 responsiveness. Oops, sorry. Um, Within this population of patients, this is a normal, uh, bold response to a, this is a very small change in CO2, but the whole brain lights up with increased cerebral blood flow. This is an abnormal brain with regional areas of uh abnormal cerebral vascular reactivity at risk for intracranial steel during changes in CO2 during anesthesia. And these are the kind of small changes you can see in older patients, um, without, with a mild neurocognitive defects, you can get some white matter abnormalities. Oops. So in this very preliminary uh study, they showed that the factors that were not associated with delirium in this group of patients was either the anesthetic agent or the duration of anesthesia, but the factors that were associated with delirium was age of the patient, the existence of preoperative cognitive dysfunction or psychiatric disorders, an abnormal MRI or an abnormal abnormal MRI CO2 stress test. Combined with intraoperative factors, um, such as a, a decrease in, uh, a change in cerebral CO2 of more than 10 to, hypotension, and a, a decrease in cerebral saturation during the course of the anesthetic. These are very, this was obviously a very preliminary study and with small numbers, they're looking at it as over a much larger number of patients, but they proposed that this suggests a stress diathesis model, that there are patients who come to the operating room with preoperative neurological and cognitive vulnerabilities, that those patients in combination with the stress of surgery and anesthetic, uh. dynamic and CO2 abnormalities might be those patients at risk for um postoperative cognitive dysfunction and suggests that the, the conduct of anesthesia in the context of a vulnerable vein is probably as important as the anesthetic agent itself. That suggests to me that we can translate at least some of these concept concepts to the pediatric population. Whereas, where there are children with neurocognitive vulnerabilities, we can think about things like children with pre-existing lesions, with inflammation, with neurovascular immaturity, with, um, during the period of neurogenesis. We know that neonates, for example, have, have, uh, impaired auto regulatory control and are exquisitely sensitive to CO2 and hypotension changes in the operating room. Mary Ellen McCann has raised that as an issue in Certain groups of patients with postoperative abnormalities. That those patients combined with the stress of surgery and anesthesia in the entire perioperative period, which might include the anesthetic agent, but we probably also need to look at all the other things that go along in the conduct of anesthesia, including uh uh determinations of what constitutes normal CO2 swings during anesthetics, what is a normal hemodynamic response during anesthesia by age. Uh, uh, Probably looking at cerebral saturations and some markers of inflammation might be as relevant as the anesthetic agent per se, and use that in combination might be associated with either early or late changes in cognitive function. Interestingly, Warner and Fleck just in a recent editorial that came out before their mass trial, these are, these are the, this is the group of people that did the mass trial. have raised the same sort of framework to try and put anesthetic neurotoxicity in context of the entire um periprocedural factors. This to me, the, the framework that they proposed to look at this going forward is quite similar to the stress diathesis model that uh you need to look at um anesthetic exposure in In the context of the child characteristics, the procedure uh being undertaken, the anesthetics themselves, uh, and the external environment. And that that might all have influences on early evolving responses that, that they too then might modulate, they might worsen, they might improve long-term responses. This makes a much more complicated, uh, study to do in terms of trying to tease out all of these factors, but this is probably where we need to be going from now on. So going forward, I, I think that, you know, from the, from the trying to put all this data together at this stage of the game, pre-clinical models serve a, a very useful function in terms of hypothesis generators. We still need to look at ways to correlate structural abnormalities with specific behavioral outcomes. That they can probably help to define relevant biomarkers or imaging tools that we might be able to use to translate into children. But we definitely need more human models and move to human models, looking at more extensive longitudinal studies, defining vulnerable populations with either MRI testing, biomarkers, precognitive cognitive testing, which is pre-op testing, which has never been done in children um before the exposure to anesthetic. I think we need to look much more closely at the conduct of anesthesia. And, and has been suggested by many people to have parallel studies trying to define what constitutes a normal blood pressure under anesthesia in children, uh, and normal hemodynamics, and look at the whole perioperative period in terms of stress response, inflammation, the nutritional environment of the child, um, The family structure of the child, the enrichment that the child lives in, um, before we can help sort of move this forward. So just in in ending, uh, lots of the lots of the thinking was that Hercules attacked the Hydra by himself, however, he didn't. The, the real truth is that he couldn't defeat the beast by himself. Every time he cut off a head, it grew back too. He needed to, he needed a collaborator, he needed Aeolus, who was his trusty companion who thought to cauterize each of those heads after it was chopped off and prevent its regrowth. So I'm suggesting that moving forward, this is gonna require an awful lot of collaborative effort for us to slay this hydra beast of neurotoxicity. And move on to maybe the Cretton Bowl. Thank you very much. Well thank you Ruth for your because you're task of trying to uh decipher all the clinical studies that are involved in this. Uh, this is, this, uh, talks now open for questions or comments, Paul. So Ruth, that was by far the best. Survey of the whole neurodevelopmental question that and it put it into the context which made it much clearer that we are talking about how many angels can dance on the head of a pin and we focus on anesthetic and not on all the other things which have a much bigger factor. And are much more controllable in terms of neural development in young children. So I assure you that from my perspective, you've more than than met the test of presenting a really great lecture and pulling a huge amount of information together. Thank you so much. Thank you. I think, you know, one of the things that I've learned most about this is how huge the social determinants of health are in terms of growth and development of children. And, you know, if we really want to help kids, let's deal with poverty, you know, let's let's deal with nutrition, let's let's make kids live in safe environments, you know, it's, to me, that's a hugely important factor. Uh, I also agree. I thought it was a great talk. I have a question as an educator, because 30 years ago when I was training, we were taught to overventilate patients that were, uh, that were breathing, right? I still come across that almost monthly. So clearly, our adult compatriots are still teaching what we were taught incorrectly 30 years ago. Have you given any thought as how we can change that? I have no idea, you know, but if, it, it, I'm just horrified that what we did 30 years ago, to tell you the truth, we gave 100% oxygen to babies to make sure that SAT stayed up. You know, I think part, part of the, part of the, the burden of anesthesia is the, and, and the benefit of our new monitoring, you know, that like that in as much as SAT monitoring has been a huge boon. We also are at risk of hyperoxyation, probably more than hypoxia under anesthesia these days, and we don't even think about it. And likewise, CO2 monitoring gives us a measure of uh comfort without real accuracy in with kids, you know, so I, I wish I had an answer to that because I do, I agree with you absolutely, you know. Uh, Karen, Oh, yeah, that was a wonderful talk and, uh, just, you know, really puts everything into, into perspective. Uh, I happen to be a, a, a, um, biased, strongly biased proponent of regional anesthesia, you know, disclosure, and, uh, I, I. The use, the concurrent use of regional anesthesia decreases, dramatically decreases exposure to general anesthesia. Since you do continue to show that there are small differences associated with the exposure of general anesthesia, what is your, um, we Happen to have the ability to provide regional anesthesia here to almost every child who, uh, could have it. What's your advice on just decreasing the exposure to general anesthesia in a dose-dependent fashion, if not in a numeric fashion? I, I, I'm for it. What can I say? I mean, I, you know, I, I, I, I think sort of combined techniques and sort of mini minimizing pain responses and, I mean, there's all sorts of other things that go into a combined regional general anesthetic, that's not just anesthetic exposure, that's probably also of relevance, you know. But why not, you know. Is anyone looking, I mean, now you're doing all these studies with 100,000 kids, 50,000 kids, instead of just saying one exposure, two exposures, are they breaking it out into total duration of exposure? You know, uh, the, the mask trial was able to do that, looking at total exposure and didn't see a difference. The trouble with the, you know, the, the trouble with huge epidemiological studies, it gives you huge numbers with not granularity, so you can't look at things like that, you know, using those numbers, where you need, if you're gonna look at very subtle effects, you need huge numbers to To, to explain differences, but we don't have the, the anesthetic exposure times to be able to know that, or whether or not, you know, or looking at combined regional and general, for example, you know. So Karen, I guess you're, you're implying that we should change our byline to until every child gets a blocked, right? Uh, Susan, hi Ruth. Um, so nice to see you. Thank you for an amazing talk. I was hanging on every word and I agree that you summarized the topic very well. I've seen this presented almost at every anesthesia meeting, um, and, uh, and that was a great summary. My question is, do we now have enough evidence to go back to the FDA because we have that hanging over our heads, uh, and, and. Uh, you know, petition them to change that, their previous recommendation number 1, and number 2, I just saw, um, Warner present the mass trial at the IRS last week, and he seemed to suggest that we're, we may be testing the wrong thing, as you said, they found differences in the fine motor and the behavior, and so, you know, how does that, uh, you know, incorporate into where we go from here. It, well, I mean, both really interesting questions. Um, I Actually opened my, I was at the last panda conference, uh, symposium with Mary Ellen and with Saul, and I actually asked that question that that perhaps we've been a bit premature with the FDA announcement, you know, given all these facts and we're sort of changing behavior, is this really Was this relevant? Was this, is this something that, that, uh, the FDA was not very happy with that suggestion, so it's certainly from their point of view, I mean, in fairness, they need to be conservative, they need to be concerned. They said their whole goal was to Inform people so that discussions happened with families so that they were clear about things. I get that. I, um, but I don't, I think it's the FDA is a very conservative, slow moving, uh, entity, so I think the ability to go back on that is, uh, pretty small. To add to that point, Mary Ellen and I have sat in the FDA advisory committees, and they really have to base their data on the animal studies because that's work from their own group. And they again they had to be very conservative in this. It's just to be as clinicians to be able to interpret it and be able to apply it to our patients and show some reason and how it affects clinical practice, but they, they have some rigid findings in their own group about the, the pre-clinical studies showing there's some toxicity involved. So that's what their stance is. It'll take a while for them to change that. So, uh, but, and what about the, we should be testing more fine motor and behavior. You know, if you believe the monkey studies as well, they certainly moved to looking at an anxiety phenotype as opposed to learning and, and memory. It, it, maybe we do, but maybe anxiety is, and, and those kinds of things are entirely related to the whole peri-procedural experience too, you know, like a post-stress response. Ruth, that was fantastic. Can you comment on this, on the position of the Canadian and European regulatory authorities? So they, so they tend to always, uh, you know, I don't know what the Europeans have done. The Canadians just came out with a, with a very similar statement to the FDA just within the last 6 months. We just, uh, drafted a response to them similar to what the ASA drafted, you know, and the, and the, the SPA saying that there needs to be concerns. The, the, the problem with having, uh, it's, I just consider this a huge problem, not because they don't need to inform people, but because of the media response to this has created the, uh, you know, as, as if parents aren't anxious enough bringing their children to have a a a procedure done, and now you, you were sort of having to justify the need to give anesthetics in a safe a way as possible. With with people thinking that we're destroying their children's brains. It's a, it's a horrible position to be. I don't know, do you guys find, I find it horrible to try and sort of be be reassuring. And, and, and providing enough information so that people can actually go ahead and give their child to you, you know, for a procedure that needs to be done. Yeah, Chuck, um, the, our European colleagues have been fairly clear about this. They published a consensus statement from the European Society of Anesthesia, European Society of Pediatric Anesthesia, and Eurostar, which is the basic science component of this, and they clearly stated in their consensus statements published in the European Journal of Anesthesia as well as, uh, pediatric anesthesia that The finding that anesthetizing patients less than 3 years old was unfounded on both clinical evidence as well as some of the subtle changes in the pre-clinical studies. So they're fairly clear about it and they've actually developed a somewhat support group among clinicians called Safe Thoughts. So you can look it up, Safe Thoughts. Dot org and you'll see some of the supporters of their statements there, right? I just didn't know if the European Medicines Agency followed that or not. I don't know if anyone knows. They published a consensus statement. You can look it up. That's not from the agency. That's from professional societies, professional societies, yeah. Any good questions? How about the whole issue about chronic illness? Um, um, you know, some, when, when you have these multiple uh uh exposures, sometimes you're thinking it may be just the whole revisit, uh, revisitation of chronic illness as it impacts your development. Uh, I think something that's, um, has to be addressed as well, you know, if you obviously have required multiple surgeries for, for these, um, lesions, so to speak, they certainly are exposed to a chronic illness environment which will impact your neurodevelopment. That, you know, there were some, there were some studies done looking at chronic medical illnesses, diabetes, um. Cystic fibrosis, I can't one other which, which suggested that those kinds, those types of chronic illnesses weren't associated with major, you know, brain development abnormalities, interestingly, you know. Yeah. But as you pointed out, even if you take the secondary analysis where having eye and ear surgery is different than a hernia, not seeing and not hearing early in life is, is a problem, and having surgery to correct them is better than not doing so. Exactly, exactly. Like what, you know, in, in our study, we, we deal with a very underprivileged population, so the kids between 2 and 4, a huge number of those kids were having dental procedures, if you can believe it, you know, but these kids have teeth that are completely rotted out of their heads, so they're not having 2 teeth filled, they're having an entire mouth, uh, fixed. And they, uh, the dentists, actually one of the academic dentists is looking at nutritional deficiencies, you know, so the question of fixing their teeth might improve their nutritional status and their chronic inflammatory state, you know, from their chronic infection, which might be a good thing as well. All those are, those are probably the kids that had the most, that were most responsible for the for that, those small changes we saw in our study, you know. Well, it's uh 7:59. It's time to go back to the To the, the, the dungeons and uh thank you very much and uh Doctor Brown will be around today for um as a visiting professor and she'll have another seminar at 5 o'clock addressing the whole issue about uh blood pressure management.