Date Published: April 19, 2019
Publisher: Lippincott Williams & Wilkins
Author(s): Graham J. Walkden, Anthony E. Pickering, Hannah Gill.
Neurodegeneration has been reported in young animals after exposure to all commonly used general anesthetic agents. The brain may be particularly vulnerable to anesthetic toxicity during peak synaptogenesis (in gestation and infancy). Human studies of long-term neurodevelopmental outcome following general anesthesia in early childhood report contradictory findings. This review assesses the strengths and deficiencies in human research methodologies to inform future studies. We identified 76 studies, published between 1990 and 2017, of long-term neurodevelopmental outcome following early childhood or in utero general anesthesia exposure: 49 retrospective, 9 ambidirectional, 17 prospective cohort studies, and 1 randomized controlled trial. Forty-nine studies were explicitly concerned with anesthetic-induced neurotoxicity. Full texts were appraised for methodological challenges and possible solutions. Major challenges identified included delineating effects of anesthesia from surgery, defining the timing and duration of exposure, selection of a surgical cohort and intervention, addressing multiple confounding life course factors, detecting modest neurotoxic effects with small sample sizes (median, 131 children; interquartile range, 50–372), selection of sensitive neurodevelopmental outcomes at appropriate ages for different developmental domains, insufficient length of follow-up (median age, 6 years; interquartile range, 2–12 years), and sample attrition. We discuss potential solutions to these challenges. Further adequately powered, multicenter, prospective randomized controlled trials of anesthetic-induced neurotoxicity in children are required. However, we believe that the inherent methodological challenges of studying anesthetic-induced neurotoxicity necessitate the parallel use of well-designed observational cohort studies.
Perhaps the greatest challenge to studying anesthetic-induced neurotoxicity is in separating direct toxic effects of general anesthesia on the brain from indirect effects of anesthesia (disturbance of normal physiology, eg, hypoxia, hyperoxia, hypotension, and hypothermia),30 surgery (stress response31 and systemic inflammation), and the perioperative course (complications, pain,27 artificial or inadequate nutrition52). We illustrate this concept in Figure 2A.
Although brain structure and function develop throughout childhood, a period of peak synaptogenesis in early childhood has strong implications for later cognition, language, and social behavior.6,39 Exposure during this “vulnerable time window” of brain development ought to be the focus of anesthetic research. Although its timing is well defined in animal species, with the overwhelming majority of studies performed on postnatal day 7 in rats,11,32 human anesthetic-induced neurotoxicity studies have quoted a heterogeneous range of definitions, eg, “third trimester to 2 years,”8 “third trimester to 6 weeks,”9 “0–36 months,”33 “early gestation through to infancy,”10 or “birth to 2–3 years.”57 The concept of a single vulnerable time window may be an oversimplification since there are significant regional differences in the timing and pace of peak synaptogenesis,32,58 which are reflected in discordant results for different domains of neurodevelopment.34,59–61 Furthermore, the age of the neuron as opposed to the age of the child can determine vulnerability to anesthetics.46,62 At present, it seems pragmatic to investigate general anesthesia exposures up to 3 years of age.
In observational studies, selection of participants in terms of their diagnosis/disease and surgical procedure ought to minimize “confounding by indication”—a scenario in which the disease or the surgery itself is an independent risk factor for poor neurodevelopmental outcome. Studies of neurosurgical and cardiothoracic surgical cohorts,35,74 as well as children operated on with major congenital or chromosomal abnormalities52,75 are classically affected. However, studies of general anesthesia for neuroimaging,21 some otorhinolaryngology procedures (eg, adenotonsillectomy for obstructive sleep apnea associated with learning difficulty40,76 or myringotomy and grommet insertion associated with speech/language delay77), pyloromyotomy associated with significant hyperbilirubinemia32 or nutritional inadequacy,72 gastroschisis,60 craniosynostosis,30 and cancer surgery47 may be similarly compromised.
The association between general anesthesia and neurodevelopmental outcome is heavily confounded by factors throughout the life course (Figure 2B; Table 2). Properly conducted randomized controlled trials should evenly distribute known/measured and unknown/unmeasured confounders across groups at randomization, thereby overcoming confounder bias.
In utero or early childhood exposure to a range of neurotoxicants (eg, metals, organic solvents, pesticides) can adversely affect neurobehavioral development.110,111 Ethanol, like anesthetic agents, acts at γ-aminobutyric acid and N-methyl-d-aspartic acid receptors and causes neuronal apoptosis in the developing brain.92 Robust detrimental associations between heavy and binge prenatal alcohol exposure and adverse child neurodevelopment are established.112,113 However, studies of light-to-moderate prenatal alcohol exposure have suffered from residual confounding and have reported inconsistent conclusions even with sample sizes in the order of 10,000 children. We can presume that large samples will similarly be required to reliably detect any long-term neurotoxic effects following childhood general anesthesia—an effect that may also be comparable or small relative to the effects of confounding factors.9,25,39,47,73,82 Large samples are also required to permit adjustment or matching techniques to account for confounding. Existing anesthetic-induced neurotoxicity studies vary in size between 15 and 125,000 subjects with a median 131 children (interquartile range, 50–372), so are often likely to be underpowered and potentially falsely reassuring.
The neurodevelopmental outcome measures reported in the literature vary and encompass (a) intelligence/cognition, (b) academic achievement, (c) development/behavior, and (d) neuropsychiatric diagnoses, ie, attention-deficit/hyperactivity disorder, autism spectrum disorder, and learning disability.49 Prospective evaluation in multiple domains of development using a battery of sensitive, validated outcomes and trained, blinded assessors is the gold standard. However, the risk of detecting spurious associations increases with multiple outcomes. Therefore, it is wise to caution against the overinterpretation of solitary detrimental associations in the context of a panel of otherwise reassuring results.
The time interval between anesthesia and first neurodevelopmental assessment must be sufficiently long to distinguish long-term neurotoxic effects from short-term postoperative cognitive-behavioral changes (ie, ≥6 months46). It must also allow sufficient latency for marginal neurodevelopmental deficits to manifest in domains of development, which emerge, differentiate, and are amenable to thorough neuropsychological testing at older ages, eg, cognitive skills such as language/speech/reading, mathematics, memory, and executive functioning from late childhood.14,24,33 Furthermore, neurodevelopmental evaluation in school children is known to be more robust and predictive for adulthood than when measured in preschool children because of the variability in young children’s developmental trajectories.14,22,24,52,60 There has been concern that multiple life course factors may dilute any differences in outcome between exposed and unexposed children after such long follow-up. However, subtle associations between starting school in January versus December and educational achievement and intelligence quotient scores have been detected in large cohorts as late as 18 years old.47 Existing studies of anesthetic-induced neurotoxicity follow up children until a median age of 6 years (interquartile range, 2–12 years).
Despite considerable interest and anxiety, there is at present no conclusive evidence or consensus that general anesthesia harms the developing brain. Childhood general anesthesia typically comprises single short exposures and is likely to carry low risk.14,33,120 However, if general anesthesia is thought to pose long-term neurodevelopmental risks, then the impacts on clinical practice could be far reaching.
Despite growing international concern that general anesthesia in childhood leads to long-term neurodevelopmental impairment, delineating general anesthesia–induced effects from those of surgery remains a significant challenge in the study of anesthetic-induced neurotoxicity. Deficiencies of existing research also include inconsistent exposure definitions, selection of cohorts with independent risk factors for impaired neurodevelopment, extensive confounding, the need to detect subtle neurotoxic effects, blunt neurodevelopmental assessment tools, and sample attrition over the long-term follow-up required.
Name:Graham J. Walkden, MBChB.