Anesthesia and the developing brain

Myron Yaster MD and Lynne G. Maxwell MD

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

A fundamental question that has rocked our profession for the past 20 years: “Do our commonly used general anesthetics produce brain damage in infants?” or perhaps more simply put “is it safe”?  To be honest, we are unconvinced that the evidence supports the contention that general anesthesia is unsafe in the very young.  Indeed, we thought the stake had finally been put into the heart of this vampire by the GAS(1), PANDA,(2) and Mayo clinic (MASK) studies(3) and by Phil Morgan’s paper questioning many of the rodent laboratory studies upon which this whole line of research is based. (4)

Today’s Pediatric Anesthesia Article of the Day is by the very best researchers in pediatric anesthesia practicing today, so we will summarize some of the key points.  This review “describes consensus and disagreement among experts, summarizes preclinical and clinical evidence, suggests pathways for future clinical research, and compares studies of anesthetic agents to other suspected neurotoxins”.

“In attempting to translate preclinical data to humans, there are strengths and limitations to each animal model.  Choosing appropriate outcomes that are relevant and translatable represents an ongoing challenge.  Additional caveats of extrapolation between animal models and humans include physiologic monitoring issues, the developmental stage at the time of drug exposure, the length of exposure, and the absence of surgery and resulting inflammation.” Indeed, “many of the laboratory defects are simply not found in humans”.  Finally, as Morgan et al(4) point out, many of the laboratory studies demonstrating neuro apoptosis and developmental problems report only the survivors of the study conditions(5) and do not reported that in reality, the majority of animals actually died during the experimental protocol. If most of the animals died, why should we be surprised that brain injury occurred in the survivors? (Indeed, there will be more on this in a future PAAD that will be posted in the near future).

The human studies(1-3) like some primate studies have found “small behavioral score differences but no differences in intelligence in infants exposed to general anesthesia”.  Nevertheless, “there remains a possibility that anesthetic agents may cause a relevant long-term neurodevelopmental effect in children”.  The authors propose future studies to delineate this possibility including the T REX study which evaluates children undergoing longer durations of anesthetic exposure.(6)

Finally, the authors point out that “uncommon events in large populations are difficult to study using traditional methods such as randomized controlled trials and prospective cohort studies. These situations are common in areas of public health such as environmental toxicology (think lead poisoning). In these settings, the application of causal theory can help establish the plausibility of a causal link between an exposure and an outcome”.  Unfortunately, “the challenge remains that in most observational studies, the anesthetic exposure cannot be completely isolated from the rest of the perioperative experience, inflammation, and comorbidities associated with surgery” or with socioeconomic status.

The methodologic issues with this type of research and outcome measures are many and discussed in much detail in this review.  Of course, more research continues and needs to be done. However, in the interim, we both believe that whatever the negative effects of general anesthetics may be they pale in comparison to the failure to provide anesthesia and pain relief for children undergoing surgery.

Myron Yaster MD and Lynne G. Maxwell MD

  References

1.           McCann ME, de Graaff JC, Dorris L, Disma N, Withington D, Bell G, Grobler A, Stargatt R, Hunt RW, Sheppard SJ, Marmor J, Giribaldi G, Bellinger DC, Hartmann PL, Hardy P, Frawley G, Izzo F, von Ungern Sternberg BS, Lynn A, Wilton N, Mueller M, Polaner DM, Absalom AR, Szmuk P, Morton N, Berde C, Soriano S, Davidson AJ. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet 2019;393:664-77.

2.           Sun LS, Li G, Miller TLK, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, Maxwell LG, Youn A, McGowan FX. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA 2016;315:2312-20.

3.           Hu D, Flick RP, Zaccariello MJ, Colligan RC, Katusic SK, Schroeder DR, Hanson AC, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Warner DO. Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort. Anesthesiology 2017;127:227-40.

4.           Johnson SC, Pan A, Sun GX, Freed A, Stokes JC, Bornstein R, Witkowski M, Li L, Ford JM, Howard CRA, Sedensky MM, Morgan PG. Relevance of experimental paradigms of anesthesia induced neurotoxicity in the mouse. PLoS One 2019;14:e0213543.

5.           Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. JNeurosci 2003;23:876-82.

6.           Szmuk P, Andropoulos D, McGowan F, Brambrink A, Lee C, Lee KJ, McCann ME, Liu Y, Saynhalath R, Bong CL, Anderson BJ, Berde C, De Graaff JC, Disma N, Kurth D, Loepke A, Orser B, Sessler DI, Skowno JJ, von Ungern-Sternberg BS, Vutskits L, Davidson A. An open label pilot study of a dexmedetomidine-remifentanil-caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study. Paediatr Anaesth 2019;29:59-67.