Reader Response

Myron Yaster MD

As I expected, the recent PAAD on Anesthesia and the developing brain would generate a robust reader response. For those of you who missed it here is last week’s article (and spoiler alert another PAAD on this issue will be posted in the next 2 weeks):

Review Article

Caleb Ing, David O Warner, Lena S Sun, Randall P Flick, Andrew J Davidson, Laszlo Vutskits, Mary Ellen McCann, James O'Leary, David C Bellinger, Virginia Rauh, Beverley A Orser, Santhanam Suresh, Dean B Andropoulos.  Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.  Anesthesiology. 2022 Mar 1;136(3):500-512. PMID: 3501580

Randy Flick, an author of the article and a frequent contributor to the PAAD responds:

Randy Flick MD

The issue of the effect of anesthetic exposure on the developing brain is both complex and instructive.  Let me say that although the manuscript does indeed include some great scientists, I do not consider myself to be among them.  I would be remiss if I did not highlight the contributions of Caleb Ing to the field and to the publication of this paper.  Imagine herding the “cats” that are the authors to create a coherent narrative.  Well done Caleb!

Now, to the issue at hand.

As one might expect I have given more than a few talks about the question of anesthetics and neurodevelopment and as you might also expect those lectures have evolved as our understanding has evolved. The title of my current lecture is: Anesthetic Related Neurotoxicity in Children; A Saga in Four Acts.  Although your commentary quite nicely highlights the evolution of the issue, it might be instructive to briefly touch on the Four Act’s as they may provide some additional insight and useful lessons.

Act I - Dueling Editorials 

In this act, preclinical (rodent data – suspect then and now) was first brought to the attention of the peds anesthesia community through the work of John Olney and his colleagues in St. Louis.  The editorials written by clinicians vigorously discounted the animal data as fundamentally flawed and not relevant to the clinical setting (sound familiar?). I too was skeptical but thankfully (and unusually) silent mostly because on one side of the debate there were data and on the other there was opinion often expressed with great certainty.  The dueling editorials faded as early studies began to appear in the journals which takes us to Act II. 

The lesson of ACT I is; Great certainty in the absence of data is a bit risky.

ACT II - Fear and The  Lessons of Sir Bradford

Act II was characterized by animal studies in multiple species (including primates) as well as the first clinical studies many of which were positive and not what I or most others expected.  As we now know these early papers were frequently positive and suggested that we had a problem.  The Wilder study and others created significant concern even fear within the ped's anesthesia community, FDA and among parents.  During the period of fear, most of those who were performing the clinical studies tried, often in vain, to inject caution into the discussion as the data were, at best preliminary and at worst deeply flawed.  Nonetheless many suggested potentially harmful delays in procedures or changes in practice.  This, of course, is where Sir Bradford takes the stage.  Sir Bradford Hill wrote the book on determining causality in observational studies.  We used his seminal paper in an editorial as a means of reinforcing the challenges associated with interpreting observational studies and pushing back on changes to practice.  Our intent was to reduce the heat and focus more clearly on the light produce by the rapidly growing number of observational studies (some positive and some negative).  It is important to point out that the studies were the best we could do at the time but certainly did not come close to establishing a causal relationship.  They did however inform the design of the better studies that define ACT III.

The Lesson of ACT II – As a truly great scientist, David Warner, admonished me on more than one occasion:  “Randy, the data are what they are”.  Our job is to focus on doing good science and stay above the fray. 

Therefore the lesson of ACT II is; Do good science and let others opine.  Or more succinctly; Talk is cheap.

ACT III – Good (better) data - less fear

In ACT III GAS, PANDA , MASK were published and provided important reassurance that the significant negative effects seen in observation studies were not seen in better designed studies.  All three studies found no difference in the arbitrarily chosen primary outcome measure, IQ.  ACT III represents the transformation of a public health concern into a research question.  But, it is a question that has as yet not been answered.  Do exposure to commonly used anesthetic agents cause lasting negative effects on the developing brain?  As Dr. Ing reminds us; although the primary outcome measure in the aforementioned studies were negative there are patterns in secondary outcomes that need to be explained before we decide once and for all that the question is settled.  Unfortunately good science takes time which then brings us to ACT IV.

The lesson(s) of ACT III  is/are – good science brings clarity…clarity reduces uncertainty (fear) and all good things come to those who wait.

ACT IV – Dueling editorials…again

This where we are today.  As this is somewhat of a quiescent period in the clinical science, we find in the absence of new data, there is a resurgence of opinion.  Editorials featuring words like, “truth” within a large graphic and titles like, “Pediatric Anesthetic Neurotoxicity: Time to Stop! ” are once again in vogue…. i.e. smoke.  Fortunately there are larger, longer and more focused studies on the horizon like TREX and imaging based studies here at Mayo and also at University of Iowa.  These studies no doubt will bring additional light and with if we are lucky a fresh breeze that will clear away some of the smoke.

The lesson of ACT IV – Good science and blowing smoke are very different things.

The Saga of the effect of anesthetics on the developing brain provides a wonderful example of how we use good (not perfect) science to incrementally, in fits and starts, mostly answer important clinical questions.  Although the saga may yet have an Act IV it is great to know that kids are indeed safe at least from the effects of brief exposures to anesthetic agents.