See Articles, p 720 and 723
In 1981, a startling article was published in Anesthesia & Analgesia: “Exposure to Halothane and Enflurane Affects Learning Function of Murine Progeny.”1 The study found that adolescent mice that had been exposed in utero to halothane or enflurane anesthesia had markedly impaired maze learning compared with unexposed controls. Decades before the discovery of epigenetics, the article even showed that, in some cases, impairments were also found in the next generation. The authors proposed further research to explore the relevance of their findings to anesthesia in humans. The article was, however, largely ignored and the authors’ proposal not pursued.
In 1999, Ikonomidou et al2 published a similarly startling article showing that transient blockade of N-methyl-d-aspartate (NMDA) receptors led to widespread neuronal apoptosis in the developing brains of rat pups. On this occasion, there was immediate alarm: could a similar effect on the brains of young humans be going unnoticed? Important research in the 1990s had shown that chronic in utero exposure to substances acting on the central nervous system can cause irreparable damage, most notably in the case of fetal alcohol syndrome.3 But the possibility was now raised that quite brief exposure to agents previously thought harmless—most importantly anesthetic agents—might also result in damage.
Over the subsequent 20 years, an extraordinary number of articles have shown consistently that exposure of infant mammals—initially rats, mice, and guinea pigs, but more recently nonhuman primates (NHPs)4—to NMDA antagonist and γ-aminobutyric acidA (GABAA) agonist anesthetic agents causes both neuroapoptosis and significant memory impairment and behavioral changes.
Pediatric anesthetists now faced a troubling dilemma. How could we reconcile the compelling animal evidence of harm, with over a century of apparently harmless anesthetic administration to children? Given the impossibility of performing prospective, randomized exposure research on human children, was there any technique that could at least look for neurobehavioral changes that might not have been immediately apparent?
In 2009, 2 studies were published that analyzed data from serendipitous large population databases.5,6 In both studies, an association was found between human anesthetic exposure at a young age and subsequent increased risk of abnormal neurodevelopmental outcome. Several subsequent studies have shown a similar association, while others have not.7 Some have also shown an association between number of anesthetic exposures (as a surrogate for greater cumulative dose) and greater severity of apparent harm.8
A recent systematic review9 highlights many of the methodological difficulties and inconsistencies that bedevil these articles. The single greatest problem is the fact that children are given anesthetics to undergo surgery or other procedures (eg, diagnostic scans), making it extraordinarily difficult to eliminate the possibility that any findings are indicative of association but not causation. All studies attempt to reduce this risk, for example, by eliminating from analysis children undergoing open-heart surgery or neurosurgery. But subtle biases may remain. The possibility that we are observing a damaged group of children, rather than the damaging effect of anesthesia, becomes more obvious as the number of procedures increases.
Serendipitous twin studies provided a second line of human research. In 2009, Bartels et al10 published an article that analyzed a large data set from the Netherlands Twin Registry. Anesthetic exposure under 3 years of age was indeed associated with reduced educational achievements at 12 years of age and increased reports of cognitive problems. But crucially, in a beautiful piece of epidemiological analysis, it was found that nonexposed members of twin pairs discordant for anesthetic exposure had equally poor outcomes with exposed members. This finding, while confirming an association, in fact refutes the hypothesis that anesthesia is causative. In 2011, a large population data analysis11 of over 10,000 twin siblings was published. In this widely quoted article, the primary finding was that anesthetic exposure under 3 years of age was significantly associated with subsequent developmental and behavioral disorders, with an increasing relative risk as the number of exposures increased. However, the article also considered 138 twin pairs discordant for anesthetic exposure. Strikingly, just as in the article by Bartels et al,10 both nonexposed and exposed members of discordant pairs had equally increased risk of a poor neurobehavioral outcome, while members of pairs concordant for exposure had an even greater likelihood of a poor outcome. It is my opinion that this article strengthened the conclusion that anesthetic exposure is associated with, but not causative of, poorer neurobehavioral outcomes in children.
Beginning around 2010, 2 groups of researchers initiated cleverly designed prospective controlled studies of anesthetic exposure in human infants or young children. The Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study,12 a multicenter trial, recruited children <3 years undergoing inguinal herniorrhaphy under general anesthesia and compared them with unexposed siblings as controls. There were no significant differences in intelligence quotient (IQ) scores in later childhood (the study’s primary outcome). The General Anaesthesia and Awake-regional Anaesthesia in Infancy (GAS) study,13 an international, multicenter trial, also recruited infants requiring herniorrhaphy. The infants were randomly assigned to receive sevoflurane anesthesia in the treatment group or awake-regional (spinal or epidural) anesthesia in the control group. The researchers have found no difference between the 2 groups in neurodevelopmental outcomes at 5 years of age, as measured by the full-scale IQ, the study’s primary outcome measure.14 Also published recently is the Mayo Anesthesia Safety in Kids (MASK) study,15 which continues the use of an extensive database of children born in Olmsted County, Minnesota. This latest study compared propensity-matched children with no, single, or multiple anesthetic exposures before the age of 3 years. In the primary outcome of IQ, there was no difference between the 3 groups.
A recent editorial16 summarizing the results and implications of GAS, PANDA, and MAYO stated that “The comfortable truth is … the likelihood that developmental anesthesia neurotoxicity may not exist in routine surgical procedures that occur in early life.” The elegance of the GAS study, in particular, has perhaps led us to downplay the spectacular achievement of doing what was thought impossible: a randomized comparison of anesthesia versus no anesthesia in a group of infants undergoing surgery. It is noteworthy too that roughly half the infants enrolled in the GAS study had been born prematurely, so were at increased risk of poor neurocognitive outcomes and therefore perhaps particularly vulnerable to any synergistic harm from anesthesia.
After 20 years of concern and controversy, one might reasonably conclude that all is well. The animal studies were alarming, but the human evidence overwhelmingly suggests that any effect of well-conducted pediatric anesthesia is insignificant or nonexistent. The many limitations and caveats of attempting to translate animal research to humans have been presented both specifically for this research field17 and for health science research more generally,18 so the apparent disparity in findings is not entirely surprising. In a recent editorial on the strengths and limitations of translation in anesthetic research, Kharasch19 cites other examples where in vitro and animal data have not translated to clinical relevance and urges caution in moving from research findings to medical certainty.
Yet to a significant degree, hypothesis has already become accepted as fact. In 2012, “SmartTots” was formed as a private–public partnership between the US Food and Drug Administration (FDA) and the International Anesthesia Research Society (IARS) to “coordinate and fund research with the goal of ensuring safe surgery for the millions of infants and young children who undergo anesthesia and/or sedation each year.”20 From its inception, the organization emphasized the need for research funds to find ways to mitigate the deleterious effects of anesthesia on the developing brain. In 2016, the FDA warned “that repeated or lengthy 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.”21 The Australian Therapeutic Goods Administration (TGA) published similar advice in 2018.22
In 2017, the September edition of the British Journal of Anaesthesia included a special section: Anaesthetic Neurotoxicity and Neuroplasticity. The lead editorial23 states that “new anaesthetic regimens and drug classes need to be developed to minimize neurological morbidity for patients of all ages” and talks of “mitigating the adverse effects of anaesthetic exposure.” It states that “much more work needs to be done to investigate the impact of anaesthetics on neurodevelopment.” Another editorial24 suggests that, in moving to the acceptance that anesthesia is indeed harmful, we are in the middle of a paradigm shift of the type discussed by Thomas Kuhn25 in his seminal book “The Structure of Scientific Revolutions.”
All these leading sources of expert opinion either state or strongly imply that the harmful effects of anesthesia on the developing human brain are proven. The importance of this cannot be overstated, because it is from this false foundation that new research and new concerns arise. Thus begins the quest for new, less harmful, drugs39; the search for ways of ameliorating the effects of our current drugs; the search for biomarkers for harm. There is research into dexmedetomidine, melatonin, lithium, and Coenzyme Q10. Ever more concerns are raised: could early childhood anesthesia be implicated in the development of autism, anxiety disorders, attention deficit hyperactivity disorder (ADHD)? A recent mouse study suggests that the effects of neonatal sevoflurane exposure can be transmitted to the next generation by an epigenetic mechanism,26 inevitably raising concerns that this might also be the case in humans.27
Reviewers of the GAS and PANDA findings caution that, while a single brief anesthetic exposure appears safe, some uncertainties remain.28 Other commentators have emphasized the possibility of harm from prolonged or multiple anesthetic exposures,29 hypotheses which can never be disproven. A “35-minute exposure” safe limit has been proposed.30 A recent editorial postulates that we are in fact only at the beginning of the investigation of pediatric anesthesia and subsequent neurodevelopmental problems.31
In 2011, Thomas et al,32 in an editorial in Anesthesia& Analgesia, cautioned that anesthetic neurotoxicity would be “a difficult dragon to slay,” lamenting “the sometimes alarmist rhetoric, in both the medical and lay press, surrounding this issue.”
Weiss et al,33 in a 2013 editorial in Pediatric Anesthesia, stated that it is “anesthetists rather than anesthetics (that) are the threat to baby brains.” The authors lamented that an undue focus on the safety of anesthetic drugs was detracting from an examination of the factors that contribute to the safe conduct of pediatric anesthesia. In response, the authors and other leading pediatric anesthetists have formed the “Safe Anaesthesia for Every Tot” (SafeTots) initiative,34 which focuses on the safe administration of anesthesia to children.
In a 2016 editorial in Acta Anaesthesiologica Scandinavica, Hansen and Lönnqvist35 summarized the views of many when they advised us “to relax, because if it really was that harmful to be anesthetized in early life, we would most likely have suspected this phenomenon ages ago.”
In my hospital, a 2 year old recently came to the operating theater for plastic surgery repair of a minor hand injury. One parent was a medical practitioner; both parents expressed grave fears about potential anesthetic damage to their child’s brain and insisted that the repair be performed under local anesthetic alone. More than an hour and many tears later, the child was given a 10-minute general anesthetic and the procedure was over. Scenarios like this are becoming more common—not surprisingly, when parents read headlines such as “Kids exposed to general anesthetic do poorer on numeracy, literacy tests”36 or “Researchers warn on anesthesia, unsure of risk to children.”37
Unnecessary parental anxiety is but one of many costs resulting from the ongoing pediatric anesthesia neurotoxicity controversy.
Researchers and experts have been careful to indicate that “we are not certain” about the seriousness of the problem; that parents should not be “unduly alarmed.” Yet at the same time they have left enough doubt and concern to ensure a steady flow of research interest and funding. Every research dollar devoted to pediatric anesthetic neurotoxicity is a dollar not spent on research elsewhere. And it has been a lot of research. In 2016, Lin et al38 identified over 440 animal studies, with a continuing increase in the rate of publication. In a recent magisterial review of the human research to date, Walkden et al39 found 76 clinical studies of neurodevelopmental outcome after early childhood or in utero anesthesia.
The minds of many of the best researchers in anesthesia and associated basic sciences are thus devoted to the field. But neither funds nor researchers are unlimited; we must recognize that an unjustified research commitment in one area has an opportunity cost for other, perhaps more valuable, areas.
Research animals are a precious and unique resource. It has been argued that 1 benefit of ongoing animal research into anesthetic neurotoxicity is new insights into the elusive mechanism(s) by which anesthetic agents act. Insights that have arisen are undoubtedly valuable, but further research is more likely to bear fruit if focused primarily on those important questions; the nervous systems of molluscs appear particularly useful for such research.40 Much of the research now involves NHPs because their brain development is the closest to humans in terms of not only timing and duration, but in terms of complexity as well.4 Ethical considerations are particularly important when using NHPs for research; a strong case has been made that there is no justification for their continuing use for research in this field.41 Even for “lesser” mammals, one cannot help but wonder whether the benefits outweigh the suffering in a study which shows “neurobehavioral abnormalities induced by repeated exposure of neonatal rats to sevoflurane can be aggravated by social isolation and enrichment deprivation initiated after exposure to the anesthetic.”42
Walkden et al39 have presented detailed proposals for further human research. Recognizing the challenges of performing randomized controlled trials in humans, they advocate “prospective or ambidirectional cohort studies that accurately ascertain general anesthesia exposure, rigorously control for confounders, and prospectively follow up neurodevelopment into adolescence”; studies designed to “elucidate the role of potential mediators and effect modifiers of any neurotoxic effect to inform strategies to mitigate the potential neurotoxic risks of general anesthesia in early childhood.” Such research—into a phenomenon that appears unlikely to exist—would be challenging and complex, with a very long time to fruition.
But what of research directed at the known risks of pediatric anesthesia? We can all agree that an important benefit of the past 20 years of discussion and debate is the emphasis that, in young children in particular, procedures requiring anesthesia should never be undertaken lightly. Recent studies have shown worryingly high rates of airway complications and even cardiac arrest in pediatric anesthesia.43,44 Major research projects can and will help us better understand and manage such risks.45 A rare but extremely serious problem is the occasional occurrence of infantile postoperative encephalopathy46; the causative factor(s) remain unclear and desperately require further research to clarify them.
It is in meeting these very real challenges that our efforts, our research, and our advocacy for our young patients should be directed.
Name: Richard K. Barnes, FANZCA.
Contribution: This author helped write the entire article.
This manuscript was handled by: James A. DiNardo, MD, FAAP.
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