Strictly Clinical
  • Anesthesia Exposure in the Young Child and Long-term Cognition: An Integrated Review

    Millions of children every year undergo seemingly safe general anesthetics for surgical procedures and imaging studies. Anesthetic agents have been shown to cause detrimental effects on brain cell survival and cognitive function in animals. As a result, the safety of general anesthetics in children is an active field of investigation. The objective of this review is to evaluate the human research on anesthesia neurotoxicity in the young child. Three databases were searched for studies on anesthesia exposure in infants and children. Positive clinical outcomes in several studies showed no difference in cognitive function between children exposed and unexposed to anesthesia. Research findings also demonstrated negative clinical outcomes following anesthesia exposure, including physical changes on magenetic resonance imaging such as lower gray matter density in the occipital cortex and cerebellum; lower scores on performance IQ, listening comprehension, and expressive language; overrepresentation in the lowest fifth percentile of academic achievement; and increased risk of learning disabilities. More studies are needed that simultaneously measure cognitive function, physical changes, and disability risk to learn how these factors interact in the human brain.

    Keywords: General anesthesia, neurotoxicity, pediatrics.

    Millions of children every year undergo general anesthetics for surgical procedures and imaging studies.1 The safety of general anesthetics in children has become an active field of investigation since anesthetic agents have been shown to cause detrimental effects on brain cell survival and cognitive function in animals.2 The preclinical evidence for anesthetic neurotoxicity in humans, derived from in vitro and in vivo animal studies, raises concern that the clinical use of anesthetic agents in children might lead to adverse long-term neurodevelopmental outcomes. It remains unclear whether animal data can be extrapolated to humans.

    Observational studies in humans have demonstrated mixed outcomes related to cognitive function in children who undergo anesthesia. In several studies, positive clinical outcomes  were demonstrated by the finding of no difference in cognitive function between children exposed and unexposed to anesthesia.3-18 Negative clinical outcomes following anesthesia exposure included physical changes on MRI, such as lower gray matter density in the occipital cortex and cerebellum; lower scores on performance IQ, listening comprehension, and expressive language; over-representation in the lowest 5th percentile of academic achievement; and increased risk for learning disability.19-37 Although these effects were not demonstrated consistently across studies, these results were compelling and warrant additional investigation.

    Many organizations have issued recommendations about the use of anesthesia in young children. Smart Tots (Strategies for Mitigating Anesthesia-related Neurotoxicity in Tots), the research initiative of the International Anesthesia Research Society, issued a 2014 consensus statement suggesting postponing surgeries and procedures that can be reasonably delayed until after age 3 years because of the potential risk of anesthetics to the developing brain (http://smarttots.org/about/consensus-statement/). However, anesthetizing and sedating children is rarely optional, and often procedures cannot be delayed safely. The Anesthetic and Life Support Drugs Advisory Committee of the Food and Drug Administration (FDA) states in committee proceedings that it would be unethical to allow children to undergo medical procedures without adequate sedation.38 In December 2016 the FDA issued a “Drug Safety Communication” stating that anesthetics used in children less than 3 years old may affect the development of children’s brains, with specific focus on procedures lasting longer than 3 hours.39

    The purpose of this integrated review is to synthesize extant human literature on anesthesia exposure in young children and its impact on long-term cognitive function. The review questions are as follows:

    1. What are the long-term effects of anesthesia exposure on the neurologic development of children?

    2. If anesthesia is correlated with negative effects on long-term neurologic development, does age at exposure make a significant difference?

    3. If anesthesia is correlated with negative effects of long-term neurologic development, does duration or frequency of exposure make a significant difference?

    Methods

    An integrated review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure).40

    Procedure. Comprehensive literature searches of the electronic databases of Cumulative Index to Nursing & Allied Health Literature (CINAHL), PubMed, and Scopus were conducted using the keywords neurotox*, neurocognit*, cognit*, pediatric*, neonat*, premature, child*, infant*, newborn*, baby, babies, anesthe*, anaesthe*, anaesthe*, anaesthe*, and sedat* as well as associated MeSH (Medical Subjects Headings) or Boolean phrases. This generated a list of potentially relevant articles that were stored in Legacy RefWorks (ProQuest LLC). Duplicates were deleted, with near-match duplicates screened by a single reviewer. Two reviewers screened titles in a double-blind process. A single reviewer searched the authors of the articles included in the review, screened the citation lists for relevant articles, and retrieved abstracts and full articles in the manner described for the previous steps. This process created a list of 26 articles. Fifteen articles were added to the review after the initial screening process through database alerts for search terms.

    • Inclusion and Exclusion Criteria. Experimental studies examining anesthesia exposure in humans aged birth to 24 years and conducted between January 2000 and July 2018 were included. All anesthesia exposure types, duration, and surgical indications, except cardiac studies, were included. All studies in which outcomes involved long-term cognitive function or brain development with measurement at any age were included.

    Excluded from this analysis were general review articles, in vitro and animal studies, publications prior to 2000, non-English language publications, and studies that did not measure cognition or brain development. Studies exclusively of children with congenital cardiac disease undergoing cardiac surgery were excluded, except when cardiac surgery was a small portion of the surgical cohort as a whole. Also excluded were studies on sedation performed in the intensive care unit, drug toxicities, prescription medications, substance abuse, and fetal (obstetric), adult, and geriatric populations.

    Results

    Forty-one articles were included in this review.

    Long-term Effects of Anesthesia Exposure. Outcome measures were divisible into 4 main categories: academic assessment, behavioral assessment and disability outcomes, brain studies, and neurologic testing using a validated neurologic assessment. Some studies found that anesthesia exposure correlated with subsequent deficits, whereas others found no correlations.

    Twelve studies used academic assessment measures (Table 1*).a Anesthesia exposure was found to negatively correlate with academic assessment in 9 of these studies, especially for multiple exposures and increased duration of exposure, with some caveats.20,24,26-28,33,35,36,41 These findings were demonstrated for children aged 0 to 4 years old at exposure, and negative outcomes were correlated with exposure to both general and awake regional anesthesia. Three of these studies found a difference only after multiple exposures but not after single exposure.24,28,35 One was a twin study that attributed the difference between exposed and unexposed twin pairs to a capture of genetic difference.41 Two studies found older ages to be associated with decreased academic achievement: 2 to 4 years and 37 to 48 months at exposure.26,27

    Nineteen articles measured behavioral assessments and learning disabilities (Table 2*).b Eleven studies found increased inattention and increased diagnosis of behavioral, learning, or developmental disorders in the exposed group with some caveats.c Five of these studies demonstrated differences after multiple but not single anesthetics.17,24,28,34,35 One study was underpowered,42 and 1 was the twin study referenced earlier.41 Eight studies did not find an association between anesthesia exposure and changes in behavior.6,10,12-15,29,42 Two studies looked exclusively at autism, which was not affected by anesthesia.6,12 Five of these studies used the Child Behavior Checklist (CBCL) or a general parental survey.10,14,15,29,42

    Four studies assessed brain structure in pediatric patients who underwent anesthesia (Table 3).5,19,43,44 Two studies examined brain magnetic resonance images of children exposed to anesthesia.5,19 Both studies showed differences in brain structures for the exposed cohort, but the anatomical areas affected differed. Backeljauw et al19 found lower gray matter density in the occipital cortex and cerebellum, which correlated with lower scores for performance IQ and language comprehension. Conrad et al5 found that although global brain variables were not significantly different for the sample as a whole, the number of surgeries was positively correlated with frontal lobe volume and negatively correlated with verbal IQ for a surgical subset of this group. Histopathologic findings of central nervous system changes on autopsy showed gliosis, a nonspecific reactive change of glial cells in response to damage in the central nervous system, was more prevalent in the group exposed to anesthesia.43 Testing with functional MRI showed no differences in accuracy, response time, or activation patterns in the prefrontal cortex and caudate nucleus but did show activation differences in other structures for children exposed to anesthesia.44 Overall, all 4 studies showed differences in the brains of children exposed to anesthesia, but the significance of these findings is unknown.

    Seventeen studies used direct neurologic testing (Table 4*).a Seven studies that varied widely in design and age of exposure showed no significant differences for children exposed or unexposed to a single anesthestic.3,5,7,10,14,16,17 These results included 3 large-scale trials: the General Anesthesia vs Awake Spinal Anesthesia (GAS) study, the Mayo Anesthesia Safety in Kids (MASK) study, and one of the studies from the Pediatric Anesthesia Neurodevelopement Assessment (PANDA) project.7,14,17 The MASK study was the only one of these to examine multiple anesthetics, and they demonstrated some neuropsychological domains were affected by multiple exposures, but these results should be interpreted cautiously.17

    Eight studies, all of which examined children who were exposed to anesthesia at less than 5 years old, found differences in outcomes, particularly in listening comprehension, performance IQ, and receptive and expressive language.11,19,25,26,29,31,37,46 One of these, which is an outlier in exposure type, examined patients who received ketamine as a solo anesthetic and found that greater than 3 exposures resulted in lower test scores.37 Zhang et al18 demonstrated a decrease in IQ scores following anesthesia for school-aged children, but the IQ scores recovered to baseline by 1 year postoperatively. Petrackova et al45 stratified participants into early (0-8 days) and late exposure (3-10 months) groups, and they found no differences between these exposure groups but did not compare them with population norms. One study’s findings were sensitive to missing data, which hindered interpretation.46 Two studies examined duration of anesthesia; 1 demonstrated that anesthesia duration was associated with incremental decreases in developmental test scores, and another found differences in procedures lasting longer than 35 minutes but not less than 35 minutes.11,31 Two studies of infants found that single surgeries for full-term infants, or preterm infants at term-equivalent age did not alter outcomes; however, surgeries for preterm infants before term-equivalent age were correlated with decreased performance and verbal IQ.3,25

    Age at Exposure. The articles included in this review had a range of ages for anesthesia exposure, from preterm to 10 years old, and outcomes were measured at ages 2 through 19 years. Three studies of children exposed to anesthesia after age 5 years found no long-term behavioral difficulties or cognitive effects, with the exception of decreased motor function in children exposed between 3 and 10 years of age, and an interim drop in IQ scores, which recovered to baseline 1 year postoperatively.10,16,18 Most of the studies focused on children less than 5 years old at exposure, with a single study extending to 7 years of age. Several studies focused on exposure in infancy. Under the age of 4 years, many studies found an association between a single anesthesia exposure and decreased cognitive function, increased incidence of behavioral disorders, and developmental brain changes as discussed earlier.19-23,26,28-31,33,43 However, the findings do not consistently show that younger children (infants or neonates) are at greater risk than older children (2- to 4-year-olds). Two studies found that the vulnerable age was the older portion of their cohorts.26,27 This is at odds with the prevailing belief that younger age at exposure is associated with greater risk and may constitute a critical window.

    Duration and Frequency of Exposure. Research findings suggested an association between duration of exposure and negative outcomes on IQ performance, behavior, and brain development. Indeed, most studies that included multiple anesthetics found changes with multiple exposures.17,21,24-26,28,33-35,37 Longer cumulative anesthesia exposure was associated with increased risk of behavioral abnormalities, learning disability, decreased educational achievement, and decreased total and expressive language scores.11,20,21,31,35 It is unclear if the impact is specifically related to duration (cumulative time in a single exposure) or frequency (discrete number of times that a patient is anesthetized) or whether it is a combination of both.

    Discussion

    The purpose of this integrated review was to describe the literature associated with anesthesia exposure in the young child and its long-term effects on brain development and cognition. The findings were mixed, likely reflecting study heterogeneity with respect to design, population, surgical procedure, outcome measures, age at exposure, age at outcome assessment, and anesthesia exposure (duration, frequency, and anesthesia type: sedation, general, or regional). Although this heterogeneity addresses small gaps in the literature, it precludes replication of findings and hinders synthesis. Additionally, differential sensitivity of the outcome measures used by multiple investigators limits cross-study comparisons. Some studies were retrospective, thus hindering the explication of causal relationships. These clinical data are also limited by several confounding factors, including the presence of comorbid conditions, varying degrees of surgical stress, the inclusion of previous-generation volatile anesthetic gases such as halothane, and the lack of modern monitoring techniques such as end-tidal gas monitoring and pulse oximetry. Surgical stress, the systemic response to tissue injury, characterized by activation of the sympathetic nervous system and immunologic, hematologic, and endocrine responses, may have an impact on the developing human brain independent of the anesthesia exposure. Anesthesia could potentially either ameliorate or aggravate this impact.

    The studies generally concluded that academic performance is negatively correlated with anesthesia exposure, especially for multiple exposures and increased duration of exposure. Academic performance is influenced by social and financial factors limiting efforts to explicate the effects of anesthesia exposure. Despite this limitation, academic performance is often measured because it represents the intersection of behavior, attention, learning, and intelligence. The methods of these studies varied greatly, with outcome measures ranging across a variety of standardized testing, from the benchmark examinations taken by all students at set intervals in their education to the academic grades assigned by their individual teachers, and across the range of elementary through high school education. Several studies, 2 of which did not find any achievement gap on testing, found increased nonattainment of academic scores, that is, scores on standardized academic tests were missing.4,8,9,26 Although the cause of nonattainment is unknown, the authors of these studies suggest that higher rates of nonattainment may indicate disability, which prohibits a student from taking these examinations.

    Behavioral findings were mixed, but those that reported negative clinical findings found associations with increased anesthesia exposures and duration, with some studies showing differences after single exposure as well. The CBCL was used in 5 studies.10,14,17,29,42 Other measures, such as medical diagnoses, International Classification of Diseases, Ninth Revision coding, and formula calculations for performance were more consistently associated with negative clinical findings than the CBCL.21-24,28,30,34,35 Because the CBCL is unique in that it measures parental and teacher observations, the variation in findings may be tool specific.10,14,17,29,42

    Awake regional anesthesia has been proposed for pediatric populations to avoid exposure to general anesthesia. Two studies examined outcomes after awake regional anesthesia.7,36 In the only randomized controlled trial included in this review, Davidson et al7 compared the administration of awake regional anesthesia or general anesthesia in infants and found no differences in neurodevelopmental outcomes at 2 years of age. Williams et al36 compared children exposed and unexposed to awake spinal anesthesia and found a small but significant decrease in math and reading scores in exposed children. This finding suggests that correlations between anesthesia and negative outcomes may not be due to anesthesia drug exposure but rather to other factors, such as medical burden or a side effect of surgery and anesthesia, such as surgical stress or hypotension, which is yet undescribed.

    Using awake regional anesthesia as an alternative to general anesthesia is problematic for practical reasons, because it is effective for only a limited range of procedures and patients. Indeed, most regional anesthesia performed in children is placed after induction of general anesthesia and is intended to enhance postoperative recovery. The failure rate for awake regional procedures is not insignificant; the GAS study found a 19% failure rate for awake regional techniques.7 There are no offsetting findings in the literature to support the use of awake regional anesthesia to avoid exposure to general anesthesia.

    Direct neurologic testing or performance IQ testing administered by trained personnel appears to be the most sensitive measure for detecting small changes in exposed children, since they allow for granular examination of the neuropsychological domains that may be affected. Compared with other outcome measures, direct neurologic testing is expensive and time consuming. The studies that have large numbers of participants and use direct neurologic testing were secondary analyses of existing databases originally created for other purposes, thus limiting conclusion validity.10,11,26,29 Three large-scale studies (GAS, PANDA, and MASK) all used these robust outcome measures.7,14,17 The strength of these studies in design and outcomes measured, and the fact that none of them found a correlation between a single anesthesia exposure and decreased cognitive function, is promising for the safety of healthy children having a single outpatient surgery.

    Future studies should use standardized outcome measures to facilitate cross-study comparisons and thus advance our knowledge. Also, studies designed to elucidate the differential effects of anesthesia frequency and duration are needed. Since adverse cognitive effects may not be detectable in every patient, future studies should incorporate latent class analysis in patient risk stratification to facilitate the development of decision-making algorithms.

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    AUTHORS

    Audrey Rosenblatt, MSN, CRNA, is employed by Rush University College of Nursing in Chicago, Illinois, and Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois. Email: Audrey_Rosenblatt@rush.edu.

    Michael Kremer, PhD, CRNA, CHSE, FNAP, FAAN, is executive co-director of the Rush Center for Clinical Skills and Simulation and a professor in the Rush University College of Nursing.

    Barbara Swanson, PhD, RN, FAAN, is an assistant dean, professor, and director of the PhD in Nursing Science Program in the Rush University College of Nursing.

    Ravi Shah, MD, is the director, Chronic Pain Treatment Program, Ann & Robert H. Lurie Children’s Hospital of Chicago.

    DISCLOSURES

    The authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request.

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