Episode #28 Anesthesia and the Developing Brain: Part 2

Hello and welcome back to the Anesthesia Patient Safety Podcast.  My name is Alli Bechtel and I am your host. Thank you for joining us for another show.

This is a special 2 part show on the developing brain and effects of anesthesia because there was just too much excellent information to cover in one show. Last week, we looked at the “What Then” content from the October 2016 APSF Newsletter article by Luke Janik, “The Effect of General Anesthesia on the Developing Brain: Appreciating Parent Concerns While Allaying Their Fears.” If you haven’t listened to that show yet, we hope that you will check it out!!

This week, we are going to talk about what’s new in 2020.

But before we dive into today’s episode, you’ve heard me recognize our corporate supporters on this show, but there’s another supporter who is absolutely essential – YOU! Every individual donation matters so much. Please visit APSF.org and click on the Our Donors heading and consider making a tax-deductible donation to the APSF.

We will hear more from Janik towards the end of the show, but first let’s return to the SmartTots.org website for a review before we get to the article. I will include the link in the show notes as well. SmartTots.org represents the collaboration between the International Anesthesia Research Society and the FDA and others who are committed to making anesthesia safer for children and infants. This is a great resource. The organization funds research designed to study pediatric anesthesia and ways to make surgery and anesthesia safer for our younger patients. The website includes information about research that has been performed in this area as well as frequently asked questions for anesthesia professionals and a separate one for parents. There are also newsletters and video presentations as well as a 2017 consensus statement on the use of anesthetic and sedative drugs in infants and toddlers.  There is still so much that we need to figure out with future research and it is really important for anesthesia professionals to carefully weigh the benefits of any elective procedure with the risks of surgery and anesthesia.

And now, let’s head back over to APSF.org. To get to the article today, click on the Newsletter heading, first one down in the current issue.  From here, scroll down until you see the article, “The Effect of General Anesthesia on the Developing Brain: Is it Time to Temper the Concern” in the left hand column.

For the updated 2020 article, Janik highlights the importance of this topic since for pediatric anesthesia professionals and parents with children who require anesthesia, the question of the safety of anesthesia exposure and neurodevelopment is paramount! Let’s turn our focus to three recent studies. Does the latest research help us to answer this vital question and how did we get here in the first place.

Back in 2016, the FDA issued a Drug Safety Communication that stated the following: “repeated or length use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.” And this warning was applied to the majority of the anesthesia medications that we use including Sevoflurane, Isoflurane, Desflurane, Propofol, Midazolam, and Ketamine as a result of abundant data from animal studies confirming the link between anesthesia exposure during early brain development time periods and neurological injury as well as adverse neurodevelopment later in life. We reviewed some of these important studies on the show last week. We cannot take these studies lightly, but it is important to realize that the data from the animal studies may not be translated to humans. Earlier clinical studies included retrospective observational studies that evaluated children who had received anesthesia at a younger age with matched controls who had not and compared levels of cognition, behavior, learning disabilities, and standardized test scores later in life. These studies did not answer the question though since the results showed either no association or some association or an association only with multiple exposures at a young age for adverse neurodevelopmental outcomes and had limitations and uncontrolled confounders.

So, what now? Great question and we might finally have an answer. In the past several years, there have been 3 landmark studies in this area and the good news appears to be that it is likely safe for children to undergo a single, short general anesthetic early in life when necessary. Let’s talk about those studies.

First, the PANDA Study is the Pediatric Anesthesia Neurodevelopment Assessment Study that evaluated global cognitive function by measuring IQ scores for healthy children between the ages of 8-15 years old who underwent one general anesthetic before they were 3 years old and compared this to their siblings who did not have the general anesthesia exposure. This was a multicenter, retrospective observational study of 105 sibling matched pairs. The sibling matching is important because it helps to minimize the confounding factors that we saw in the earlier non-sibling matched studies including genetic background, socioeconomic status, parental age/education, and family income. For the results, there was no significant difference in IQ scores between the groups and the secondary outcomes were not different between the groups too and these included tests of memory and learning, motor and processing speed, visuospatial function, attention, executive function, language and behavior.

Next up, we have the MASK Study which is the Mayo Anesthesia Safety in Kids Study that evaluated intelligence and neurodevelopmental outcomes in children who had never had general anesthesia, one general anesthetic before 3 years old, and multiple general anesthetics before 3 years old. This was a retrospective, observational study with propensity-based matching of the cohorts. The results revealed no differences in intelligence with one or more exposures to anesthesia and following a single exposure there was no difference in other neurodevelopmental outcomes. In the group that had multiple exposures to general anesthesia there was a decrease in fine motor abilities and processing speeds as well as reported increase in reading and behavioral difficulties by the parents of these children.

Moving on to the 3^rd landmark study, the GAS study. Wow, the names for these studies are all fantastic. The GAS study is the general anesthesia or awake-regional anesthesia in infancy study. We are changing it up this time because this study is a randomized controlled trial, the first and only one in this area!! Not only that, but it is an international, multicenter study that enrolled health infants who needed an inguinal hernia repair with either sevoflurane general anesthesia or awake regional anesthesia. Then at age 5 years old the children underwent intelligence testing for the primary outcomes with a secondary outcome of composite cognitive score at age 2. Last week, we talked about the 2016 secondary outcome results of no increased risk of adverse neurodevelopmental outcomes following one hour of sevoflurane general anesthesia at age2 years old. And the primary results from the study were published in 2019 and revealed no difference in IQ scores for the children in the sevoflurane general anesthesia group compared to the children who received awake-regional technique for the surgery.

That was a great literature review so now it is time to switch gears a little bit to talk about the FDA warning so we have come full circle. From 2007 until 2014, the FDA met with experts in the field to address the concern for anesthesia exposure and neurotoxicity before they issued their 2016 warning and keep in mind that the FDA warning that we talked about last week regarding the risk for anesthesia-induced neurotoxicity was issued after the results from PANDA study and the GAS study secondary outcomes that did not show adverse neurodevelopmental outcomes in older children who had been exposed to general anesthesia at a young age. The FDA warning provided information about a potential risk based on animal studies and some older observational studies while claiming that is was important to weigh the timing of the surgery and the age of the child. This FDA warning brought up some serious concerns for parents and anesthesia professionals about keep kids safe? Janik provides some examples to highlight these concerns:

Should myringotomy tubes be delayed knowing that hearing deficiencies secondary to recurrent otitis can lead to learning deficits?

Should tonsillectomy for moderate sleep apnea be delayed, when sleep apnea itself can affect neurocognitive outcomes?

If the child develops a learning disability later in life, will I be held liable for proceeding ahead? Will I be held liable for delaying?

This is a difficult conversation to have and you may have to have it in the limited time before a necessary surgery while also taking care of a child who needs to have surgery and anesthesia. It was tough to address the FDA warning and the conflicting data available on the topic in this high-stress environment. These were common conversations according to data that revealed that 60% of over 200 parents surveyed were worried about the link between general anesthesia and neurotoxicity and later developmental outcomes. A study published in 2019 in Anesthesia by Koh and colleagues revealed that the majority (91%) of pediatric anesthesiologists talked about this only when parents brought up their concerns and about 1/3^rd of the survey respondents provided information about the SmartTots.org website and their consensus statement and one third had a departmental statement that they shared with parents. In addition, this discussion was often not recorded in the medical record and it was not commonly part of the written consent either.

So, where do we stand today. Well, the data that we now have available provides reassurance that one, short, general anesthesia exposure in children less than 3 years old does not lead to worse neurodevelopmental outcomes. Research is still needed in this area to provide more information about the risks for multiple anesthesia exposures or any prolonged anesthesia exposure at a young age. Some of this research is going on right now. The TREX trial is a randomized control trial that is evaluating the standard dose of sevoflurane for general anesthesia with a low-dose sevoflurane and this trial should wrap up in 2022 to help provide information about the relationship between the dose of anesthesia and neurodevelopmental outcomes.

Janik has provided a great review of this important topic for anesthesia patient safety for our youngest patients. I asked him what he envisions for the future of pediatric anesthesia and developmental concerns. Let’s take a listen to what he had to say.

[Luke Janik] “Well, going forward, I think that we may see a shift in the research focus towards the actual conduct of the anesthetic. For instance, what is the effect of blood pressure on brain health in infants and does relative hypotension in the perioperative period have any effect on long term neurocognitive outcomes. We might ask similar questions about the role of temperature regulation and glucose regulation as well as ventilation parameters. In addition is there any way for us to measure the intraoperative risk for poor neurocognitive outcomes. What role, if any, does intraoperative electroencephalogram and cerebral oximetry have in routine pediatric anesthesia care? And can these diagnostic tools someday help us to make meaningful improvements in our anesthesia care? Are there any biomarkers or laboratory studies that could reliably help us to measure brain health intraoperatively? These are some of the many questions that I hope will someday be answered by future research.”

Thank you to Janik for his contributions to these articles and this podcast.  As we wrap up for today, here are some important considerations going forward. If you are an anesthesiologist caring for pediatric patients, it is important that you are able to talk to parents if they have any concerns and provide reassurance given the results of the recent trials. In addition, you can direct parents to smarttots.org for further information. This is an opportunity for anesthesia professionals to help parents who have concerns by providing further information and reassurance. Recent research has helped us to better understand the effects of general anesthesia on the developing brain and this is so important as we work towards our goal that no one, including infants and children, shall be harmed by anesthesia care.

If you have any questions or comments from today’s show, please email us at [email protected].

I hope that you have been enjoying listening to this podcast.  Don’t forget to subscribe to the podcast through iTunes or your favorite podcast app and we would love it if you could share this podcast with all of your work colleagues, friends, and family and don’t forget to leave us a review. Visit APSF.org for detailed information and check out the show notes for links to all the topics we discussed today.  Plus, you can find us on twitter @APSForg.  Follow along with us for additional patient safety information. And you can be part of the conversation by tagging us on twitter and using the hashtag #APSFpodcast.

Until next time, stay vigilant so that no one shall be harmed by anesthesia care.

© 2020, The Anesthesia Patient Safety Foundation