Neither a single nor repeated brief exposures to general anesthesia in young children is likely to be associated with poorer neurodevelopmental outcomes compared with no or fewer exposures.

Myron Yaster MD and Lena Sun MD

Few issues have garnered more attention in (pediatric) anesthesiology than the potential for general anesthetics to induce long-term adverse neurocognitive and behavioral effects in infants and children.  Starting in studies with traditional rodent animal models and culminating with studies in non-human primates (NHPs), there have been literally hundreds of studies reporting neuroapoptosis and neurodegenerative changes in response to multiple anesthetic drug classes as well as long-standing neurocognitive deficits.  In response to the weight of preclinical studies as well as suggestive retrospective data from humans, the US Food and Drug Administration issued a “Drug Safety Communication” in 2016 warning that anesthetic exposures greater than 3 hours may impact neuronal development in children less than 3 years of age as well as fetuses in their 3rd trimester.¹

As many of you know, I have been very skeptical of the preclinical laboratory anesthesia neurotoxicity studies and their applicability to human newborn infants (see PAAD 05/10/2022 https://ronlitman.substack.com/p/anesthesia-and-neurotoxicity-the ) Further, three large scale human studies have provided strong evidence that a single exposure to general anesthesia does not impair neurodevelopment.^2-4  Indeed, I had said very publicly at national meetings that I thought that investigators in this area were “chasing a ghost”.  Perhaps the final nail in this coffin was an article by Vaidya et al.⁵ that showed that there were no differences in long-term neurodevelopmental outcomes when comparing infants with surgical or medical NEC or SIP to controls without NEC/SIP in this study population. (see PAAD 12/01/2022 Long term outcome following NEC https://ronlitman.substack.com/p/long-term-outcome-following-nec

But what about repeated exposures to general anesthesia?  I’ve asked Dr. Lena Sun, one of the world’s experts on this topic to help review today’s PAAD by Wainwright et al.⁶ which I think puts yet another nail in the general anesthesia neuroapoptosis coffin.  Myron Yaster MD

Original article

Wainwright CE, Vidmar S, Anderson V, Bourgeat P, Byrnes C, Carlin JB, Cheney J, Cooper P, Davidson A, Gailer N, Grayson-Collins J, Quittner A, Robertson C, Salvado O, Zannino D, Armstrong FD; ACFBAL; CF-GAIN Study Groups. Long-term outcomes of early exposure to repeated general anaesthesia in children with cystic fibrosis (CF-GAIN): a multicentre, open-label, randomised controlled phase 4 trial. Lancet Respir Med. 2024 Jun 5:S2213-2600(24)00170-X. doi: 10.1016/S2213-2600(24)00170-X. Epub ahead of print. PMID: 38851197.

A human clinical trial design conundrum: How do you design a trial to study the effects of repeated exposures to general anesthesia  in which one group is randomly assigned to general anesthesia and the other to no anesthesia?  In today’s PAAD, Wainwright et al⁶ serendipitously found just such a group. In the Australian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) multi-site randomized controlled trial, patients identified with cystic fibrosis in newborn screening were randomized to either the BAL-directed therapy group which required multiple general anesthetics or standard care that did not include BAL (and general anesthesia).  “The primary aim of this extension study (CF-GAIN), using the ACFBAL cohort of children, was to determine if a greater number of general anesthesia exposures in early childhood—including the first 2 years of life, a period of time considered particularly vulnerable in human development⁷—is associated with a different neurodevelopmental or brain MRI outcome compared with fewer general anaesthesia exposures.”

“The primary outcome measure was a composite score comprised of the mean of eight subscales of the Conners Continuous Performance test, second edition (CPT-II). The composite score includes indicators of processing speed, response inhibition, and sustained attention. This measure of attention was selected because of its sensitivity to brain changes in other neurodevelopmental reports related to disease.”⁶ Patients also underwent MRIs at a mean age of 12.8 +/-1.7 years.

OK: What did they find?  “At completion of the ACFBAL trial, the BAL-directed therapy group had a median of 6·0 (4·0–9·5) exposures and the standard-care group 2·0 (1·0–4·0) exposures. At CF-GAIN completion, the BAL-directed therapy group had a median of 10·0 (IQR 6·5–14·5) exposures and the standard-care group 4·0 (3·0–7·0) exposures.   The mean Conners Continuous Performance test, second edition composite score was 51 (SD 8·1) in BAL-directed therapy group and 53 (8·8) in the standard-care group; difference –1·7 (95% CI –5·2 to 1·7; p=0·32) with similar performance on other neurobehavioural measures, including measures of executive function, intellectual quotient scores, and brain imaging.”⁶  There was no convincing evidence of structural differences on the MRI studies between the 2 groups.

“No clearly meaningful differences were observed between the group randomly assigned to receive a greater number of anesthetics and the group assigned to receive fewer general anaesthetics. Additionally, there was no sign of a dose effect on neurocognitive or behavioural outcomes. These findings suggest that repeated general anesthesia exposure in young children with cystic fibrosis is not related to functional impairment in attention, intellectual quotient, executive function, or brain structure compared with a group with fewer and shorter cumulative anesthesia durations.”⁶

These results are consistent with the single exposure GAS study.²  Of note, the “standard of care” group was not totally devoid of GA exposure.  Furthermore, the repeated exposures were of relatively short durations.   Is it therefore time to give up chasing the ghost of anesthesia in young infants and children lead to neurocognitive impairment?  What about the finding that the difference between groups in the number of children requiring learning support of being held back a school year, albeit the numbers were very small.   

Send your thoughts and comments to Myron who will post in a Friday reader response. 

Refences

1.            U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. (https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm).

2.            McCann ME, de Graaff JC, Dorris L, et al. 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 (London, England) 2019;393(10172):664-677. (In eng). DOI: 10.1016/s0140-6736(18)32485-1.

3.            Sun LS, Li G, Miller TLK, et al. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. Jama 2016;315(21):2312-2320. (In eng). DOI: 10.1001/jama.2016.6967.

4.            Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology 2018;129(1):89-105. (In eng). DOI: 10.1097/aln.0000000000002232.

5.            Vaidya R, Yi JX, O’Shea TM, et al. Long-Term Outcome of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation. Pediatrics 2022;150(5):e2022056445. DOI: 10.1542/peds.2022-056445.

6.            Wainwright CE, Vidmar S, Anderson V, et al. Long-term outcomes of early exposure to repeated general anaesthesia in children with cystic fibrosis (CF-GAIN): a multicentre, open-label, randomised controlled phase 4 trial. Lancet Respir Med 2024 (In eng). DOI: 10.1016/s2213-2600(24)00170-x.

7.            Girault JB, Cornea E, Goldman BD, Knickmeyer RC, Styner M, Gilmore JH. White matter microstructural development and cognitive ability in the first 2 years of life. Human Brain Mapping 2019;40(4):1195-1210. DOI: https://doi.org/10.1002/hbm.24439.