Episode #27: Anesthesia and the Developing Brain, Part 1

January 12, 2021

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Welcome to the next installment of the Anesthesia Patient Safety podcast hosted by Alli Bechtel.  This podcast will be an exciting journey towards improved anesthesia patient safety.

Today, we are doing another “What Then” and “What Now” Show!!  The topic today is the effects of anesthesia agents on the developing brain. The first article is “The Effect of General Anesthesia on the Developing Brain: Appreciating Parent Concerns While Allaying Their Fears” by Luke Janik. This article appeared in the October 2016 APSF Newsletter and you can find it here. https://www.apsf.org/article/the-effect-of-general-anesthesia-on-the-developing-brain-appreciating-parent-concerns-while-allaying-their-fears/

Talking to parents about children undergoing anesthesia:

  1. Many infants and children require anesthesia for relatively common procedures and there is a risk to delaying these procedures.
  2. Recent large-scale studies revealed minimal or no adverse neurocognitive development in children who underwent general anesthesia at a young age.
  3. In 2016, there was no evidence for a preferred anesthesia technique for children so the decision for the anesthetic should be determined by the anesthesia team after careful evaluation of the child and the surgery.

Click over to the SmartTots website for more information. You can find the link here. www.smarttots.org

Thank you to Luke Janik for contributing audio clips for this show.

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© 2020, The Anesthesia Patient Safety Foundation

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.

We are returning to the APSF 35th Anniversary Newsletter today, so grab a cup of coffee or go ahead and head out on your run or just sit back and relax as we open up the Jade edition newsletter once again.

Before we dive into today’s episode, we’d like to recognize Preferred Physicians Medical Risk Retention Group, a major corporate supporter of APSF. Preferred Physicians Medical Risk Retention Group has generously provided unrestricted support as well as research and educational grants to further our vision that “no one shall be harmed by anesthesia care”. Thank you, Preferred Physicians Medical Risk Retention Group – we wouldn’t be able to do all that we do without you!”

We hope that you will follow along with us and to do so, click on the Newsletter heading and the first one down is the current issue.  Then scroll down and until you see the article, The Effect of General Anesthesia on the Developing Brain: Is it Time to Temper the Concern? By Luke Janik in the column on the left. Remember, the theme for this newsletter is “what then” and “what now” so we are going to click on the original article that is mentioned right at the beginning.

In October 2016, the APSF published the article, “The Effect of General Anesthesia on the Developing Brain: Appreciating Parent Concerns While Allaying Their Fears.” We are going to start here to talk about “what then.” To help kick things off, I reached out to Janik for some exclusive content. I will let him introduce himself!

[Luke Janik] “Hi, My name is Luke Janik and I’m a pediatric anesthesiologist at Northshore University Health system in Evanston, Il and a clinical assistant professor at the University of Chicago Pritzker School of Medicine and I really want to thank you and the anesthesia patient safety foundation for having me on the podcast and for discussing this important topic with the listeners.”

I asked Janik why he wrote this article and let’s listen to what he had to say.

[Luke Janik] “I wrote about the effects of general anesthesia on the developing  brain because I noticed a fair amount of confusion, anxiety, and questions on this topic from both medical professionals and from parents. In 2016, the FDA applied a drug warning label to nearly every anesthetic agent  we use which really stoked these fears and it really created an unattended effect where we saw children at risk for not receiving necessary and timely interventions due to an unwarranted fear of anesthesia. The goal of this article was to provide a clear summary of the available scientific data and to help guide people towards reliable, trusted resources.”

This is a great introduction to the article and don’t worry we will hear more from Janik later. Let’s get started with the October 2016 article. This is an important topic since over 1 million children 5 years old and younger have surgery including myringotomy tubes, tonsillectomy/adenoidectomy, hernia repairs, and circumcisions, each year in the United States. A big question for anesthesia professionals is what are the effects of general anesthesia on a child’s brain development. Parents often have an important question too when they ask “Will anesthesia harm my child’s brain?” Before they even get to the hospital, parents may turn to google for answers to this question and be met by the following headlines: “Anesthesia May Harm Children’s Brains” from WebMD and “Researchers Warn on Anesthesia, Unsure of Risk to Children” from the NY Times.

Rather than Google, let’s turn to the medical literature and first look at Pre-Clinical data.  Janik reviews the 2000 Science article by Ikonomidou et al that looked at the role of ethanol and the development of Fetal Alcohol Syndrome. The results of administering ethanol to rat pups during peak brain synaptogenesis included generalized brain mass loss and neuronal apoptosis. The investigators reported that Ethanol causes apoptotic neurodegeneration due to NMDA receptor antagonism and GABA receptor activation. Since many anesthesia and sedative drugs act on the same receptors, this was a concerning finding.  There are hundreds of studies that describe a relationship between anesthesia drugs including benzodiazepines, propofol, ketamine, volatile anesthetics, and nitrous oxide, and neuroapoptosis in rodents and non-human primates. The big question from these animal studies is: Does the same thing happen in humans who are exposed to the same anesthesia agents? It is important to keep in mind several things. First, the dose and duration of anesthesia exposure was much higher in the animal studies then an infant would be exposed to for a typical surgery with anesthesia in the OR. Second, there is variability between the animals studied and humans in terms of drug potencies, drug toxicity, and side effects.  Third, brain maturation and the time period of brain vulnerability for brain development is different for each animal model and for humans. Finally, the animals studies may not utilize close monitoring or controlled ventilation with limited ability for resuscitation and these are important components of safe anesthesia for humans in the OR.

Let’s move from animal studies to observational studies in humans. There have been several retrospective observational studies that reported on the link between early anesthesia exposure as a risk factor for learning disabilities later in life. For example, Ing et al. looked at language test scores, cognition, motor skills, and behavior in 300 hundred 10 year-olds with anesthesia exposure before they were 3 years old compared to children without the exposure and in the children exposed to anesthesia before age 3, there was a higher risk for language and abstract-reasoning deficits. Another study by Flick et al. found that multiple anesthetic exposures before the age of 2 compared to children without exposure was a risk factor for the development of learning disabilities and a similar finding was also reported by Wilder and colleagues who looked at multiple anesthetic exposures before age 4 compared to children without anesthesia exposure.

We need to dig a little more into the literature because there have been numerous studies that do not support these findings. Hansen and colleagues found no evidence of increased learning disabilities in over 2,500 ninth graders who had an inguinal hernia repair in infancy compared to age-matched controls using standardized test scores and adjusting for known confounders. Hansen and colleagues also looked at infants who received anesthesia for pyloric stenosis repair at less than 3 months old and they had similar test scores when they were adolescents compared to the unexposed control group. Another interesting study was completed by Bartels and colleagues using monozygotic concordant-discordant twins with over 1,000 twin pairs with one twin exposure to anesthesia before age 3 while the other twin did not receive anesthesia before age 3. At age 12, the twins had similar scores on standardized tests so the early anesthesia exposure was not a risk factor for lower test scores in this study. The observational studies provide contradictory results likely due to the difficulty in controlling for important confounders such as birth weight, gestational age, parental age and education, socioeconomic status, income, and ethnicity. Even when standardized test scores are similar, there may be some neurocognitive deficits that are not apparent. Other details from the anesthesia records are often unknown for observational studies such as which anesthesia agents were used, how much was administered, and how long was the exposure.

Janik then moves on to discuss 3 landmark studies that were known about in 2016. The first one is the GAS trial or the General Anesthesia compared to Spinal Anesthesia trial which is an international, multicenter, observer-blinded randomized control trial of infants who underwent inguinal hernia repair with either sevoflurane general anesthesia or awake-regional anesthesia with spinal, caudal, or combined spinal-caudal technique. The study was scheduled to wrap up in 2017 but the secondary outcome was the assessment of neurodevelopment at age 2 in these infants and the authors did not find evidence of increased risk for adverse neurodevelopmental outcome in the general anesthesia group compared to the awake-regional group. Now, I know what you are thinking….it is 2020, so we should have the results from the GAS trial primary outcome by now. You are right, the results were published in 2019, but you will have to tune in next time to hear more about it.

The second landmark trial was by Sun et al and is the Pediatric Anesthesia Neurodevelopment Assessment Study or PANDA study. This study used sibling-matched controls to help decrease confounders and looked at neurocognitive and behavior outcomes for children who had anesthesia for inguinal hernia repair before 3 years-old and were now between the ages of 8 and 15 years-old. The results are encouraging and revealed no statistically significant difference in IQ scores as well as no difference in memory, executive function, motor and processing speed, language, attention, visuospatial function or behavior testing scores between exposed children and their unexposed sibling controls. This study also included a review of the anesthesia records.

Finally, let’s look at the study by O’Leary et al. that looked at over 28,000 children between the ages of 5-6 years-old  who were exposed to anesthesia who were compared to over 55,000 matched controls without anesthesia exposure. Janik tells us that this is the first “big data” study in this field and the results are again encouraging since the authors reported no evidence of adverse developmental outcomes in children who received anesthesia before 2 years of age or who had multiple anesthetics. One finding was interesting and will need further investigation since there was a small increased risk for adverse developmental outcomes in children exposed to anesthesia after 2 years old which is after the typical period of brain vulnerability in humans.

Before we wrap up the show today, let’s talk about the conclusions to the What Then from the 2016 article.  Janik offers suggestions for how anesthesia professionals can talk to parents about the risks of anesthesia when their children need to have surgery and anesthesia.  First, highlight that many infants and children require anesthesia for relatively common procedures and there is a risk to delaying these procedures. Second, there is some good news since the recent large-scale studies revealed minimal or no adverse neurocognitive development in children who underwent general anesthesia at a young age. And finally, in 2016, there was no evidence for a preferred anesthesia technique for children so that the decision for the anesthetic should be determined by the anesthesia team after careful evaluation of the child and surgery.

There is a really important resource for anesthesia professionals and parents alike, the SmartTots website. I will include a link in the show notes as well.  This website was created by the International Anesthesia Research Society and FDA to work together and fund research on the relationship between anesthesia and neurodevelopment. Click over to smarttots.org for additional resources including consensus statements for healthcare professionals and parents and this is something that we will talk about more in the future on this show. Janik concludes his 2016 with the following: “As anesthesia professionals, we should listen to parents and acknowledge their fears, while providing them with evidenced-based recommendations and credible resources. This may help to earn their trust, while mitigating their fears related to the effects of anesthesia on their child’s developing brain.”

Wow, that was a great article, no wonder it was picked for the 35th anniversary newsletter.  We still have more to cover to help answer the question, “What now” but you will have to tune in next time when we will talk about Janik’s updated 2020 article, “The Effect of General Anesthesia on the Developing Brain: Is it Time to Temper the Concern?” and we will be hearing more from Janik in the next show as well.

That is all the time we have for today. If you have any questions or comments from today’s show, please email us at [email protected].

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 and Instagram!  See the show notes for more details and we can’t wait for you to tag us in a patient safety related tweet or like our next post on Instagram!! Follow along with us for anesthesia patient safety pictures and stories!!

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

© 2020, The Anesthesia Patient Safety Foundation