Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

Association Between Exposure of Children to General Anesthesia and Autism Spectrum Disorder.

This study tested the hypothesis that exposure of children prior to their third birthday to procedures requiring general anesthesia is associated with an increased incidence of autism spectrum disorder (ASD) in later life. This study employed a nested, 1:2 matched-case control study design using ASD cases identified in a population-based birth cohort of children born in Olmsted County, MN from 1976 to 2000. Matching variables included sex, date of birth, and mother's age in conditional logistic regression including 499 ASD cases and 998 controls. After adjusting for birth weight and health status, there was no significant association between exposure and ASD (OR 1.27 [95% CI 0.92-1.76]), indicating that general anesthesia is not associated with an increased risk of ASD.

Moderators of the association between attention-deficit/hyperactivity disorder and exposure to anaesthesia and surgery in children.

BACKGROUND: Children's exposure to anaesthesia has been associated with risk of developing attention-deficit/hyperactivity disorder (ADHD). The goal of this study was to determine if selected patient characteristics moderate the association between exposure to anaesthesia and ADHD. METHODS: In a cohort of children born in between 2006 and 2012, exposure to anaesthesia before the age of 5 yr was categorised into unexposed, singly, or multiply exposed. Weighted proportional hazard regression was performed to evaluate the hazard ratios (HRs) of ADHD diagnosis related to anaesthesia exposure. Interaction analyses were performed to evaluate potential moderators. RESULTS: Among 185 002 children in the cohort, 9179 were diagnosed with ADHD. Compared with unexposed children, a single exposure to anaesthesia was associated with a HR of 1.39, (95% confidence interval [CI], 1.32-1.47) for ADHD. Multiple exposures were associated with a HR of 1.75 (95% CI, 1.62-1.87). In the analyses evaluating moderators of the association between exposure and ADHD, only the interaction for race was statistically significant (P=0.006); exposure increased the incidence of ADHD to a greater extent in non-White compared with White children. Among children with a single exposure, the age at exposure did not affect the relationship between exposure and incidence of ADHD (P=0.78). CONCLUSIONS: Exposure of young children to anaesthesia and surgery is associated with an increased incidence of ADHD, with more exposures associated with greater risk. Compared with White children, non-White children are at greater risk for reasons that are unknown but need to be further explored.

Effect of upper respiratory infection on anaesthesia induced atelectasis in paediatric patients.

Upper respiratory tract infection (URI) symptoms are known to increase perioperative respiratory adverse events (PRAEs) in children undergoing general anaesthesia. General anaesthesia per se also induces atelectasis, which may worsen with URIs and yield detrimental outcomes. However, the influence of URI symptoms on anaesthesia-induced atelectasis in children has not been investigated. This study aimed to demonstrate whether current URI symptoms induce aggravation of perioperative atelectasis in children. Overall, 270 children aged 6 months to 6 years undergoing surgery were prospectively recruited. URI severity was scored using a questionnaire and the degree of atelectasis was defined by sonographic findings showing juxtapleural consolidation and B-lines. The correlation between severity of URI and degree of atelectasis was analysed by multiple linear regression. Overall, 256 children were finally analysed. Most children had only one or two mild symptoms of URI, which were not associated with the atelectasis score across the entire cohort. However, PRAE occurrences showed significant correspondence with the URI severity (odds ratio 1.36, 95% confidence interval 1.10-1.67, p = 0.004). In conclusion, mild URI symptoms did not exacerbate anaesthesia-induced atelectasis, though the presence and severity of URI were correlated with PRAEs in children.Trial registration: Clinicaltrials.gov (NCT03355547).

Association Between Behavioral and Learning Outcomes and Single Exposures to Procedures Requiring General Anesthesia Before Age 3: Secondary Analysis of Data From Olmsted County, MN.

BACKGROUND: Two prior population-based (children born in Olmsted County, MN), retrospective cohort studies both found that multiple exposures to anesthesia before age 3 were associated with a significant increase in the frequency of attention-deficit hyperactivity disorder (ADHD) and learning disabilities (LD) later in life. The primary purpose of this secondary analysis of these data was to test the hypothesis that a single exposure to anesthesia before age 3 was associated with an increased risk of ADHD. We also examined the association of single exposures with LD and the need for individualized educational plans as secondary outcomes. METHODS: This analysis includes 5339 children who were unexposed to general anesthesia before age 3 (4876 born from 1976 to 1982 and 463 born from 1996 to 2000), and 1054 children who had a single exposure to anesthesia before age 3 (481 born from 1976 to 1982 and 573 born from 1996 to 2000). The primary outcome of interest was ADHD. Secondary outcomes included LD (reading, mathematics, and written language) and the need for individualized educational programs (speech/language and emotion/behavior). To compare the incidence of each outcome between those who were unexposed and singly exposed to anesthesia before the age of 3 years, an inverse probability of treatment weighted proportional hazards model was used. RESULTS: For children not exposed to anesthesia, the estimated cumulative frequency (95% confidence interval [CI]) of ADHD at age 18 was 7.3% (95% CI, 6.5-8.1) and 13.0% (95% CI, 10.1-16.8) for the 1976-1982 and 1996-2000 cohorts, respectively. For children exposed to a single anesthetic before age 3, the cumulative frequency of ADHD was 8.1% (95% CI, 5.3-12.4) and 17.6% (95% CI, 14.0-21.9) for the 1976-1982 and 1996-2000 cohorts, respectively. In weighted analyses, single exposures were not significantly associated with an increased frequency of ADHD (hazard ratio [HR], 1.21; 95% CI, 0.91-1.60; P = .184). Single exposures were also not associated with an increased frequency of any LD (HR, 0.98; 95% CI, 0.78-1.23), or the need for individualized education plans. CONCLUSIONS: This analysis did not find evidence that single exposures to procedures requiring general anesthesia, before age 3, are associated with an increased risk of developing ADHD, LD, or the need for individualized educational plans in later life.

Utility of medical record diagnostic codes to ascertain attention-deficit/hyperactivity disorder and learning disabilities in populations of children.

BACKGROUND: To develop and evaluate machine learning algorithms to ascertain attention-deficit/hyperactivity (ADHD) and learning disability (LD) using diagnostic codes in the medical record. METHOD: Diagnoses of ADHD and LD were confirmed in cohorts of children in Olmsted County of Minnesota based on validated research criteria. Models to predict ADHD and LD were developed using ICD-9 codes in a derivation cohort of 1057 children before evaluated in a validation cohort of 536 children. RESULTS: The ENET-MIN model using selected ICD-9 codes at prior probability of 0.25 has a sensitivity of 0.76, PPV of 0.85, specificity of 0.98, and NPV of 0.97 in the validation cohort. However, it does not offer significant advantage over a model using a single ICD-9 code of 314.X, which shows sensitivity of 0.81, PPV of 0.83, specificity of 0.98, and NPV of 0.97. None of the models developed for LD performed well in the validation cohort. CONCLUSIONS: It is feasible to utilize diagnostic codes to ascertain cases of ADHD in a population of children. Machine learning approaches do not have advantage compared with simply using a single family of diagnostic codes for ADHD. The use of medical record diagnostic codes is not feasible to ascertain LD.

Patterns of neuropsychological changes after general anaesthesia in young children: secondary analysis of the Mayo Anesthesia Safety in Kids study.

BACKGROUND: We hypothesised that exposure to multiple, but not single, procedures requiring general anaesthesia before age 3 yr is associated with a specific pattern of deficits in processing speed and fine motor skills. METHODS: A secondary analysis (using factor and cluster analyses) of data from the Mayo Anesthesia Safety in Kids study was conducted, in which unexposed, singly exposed, and multiply exposed children born in Olmsted County, MN, USA from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8-12 or 15-20 yr. RESULTS: In the factor analysis, the data were well fit to a five factor model. For subjects multiply (but not singly) exposed to anaesthesia, a factor reflecting motor skills, visual-motor integration, and processing speed was significantly lower [standardised difference of -0.35 (95% confidence interval {CI} -0.57 to -0.13)] compared with unexposed subjects. No other factor was associated with exposure. Three groups were identified in the cluster analysis, with 106 subjects (10.6%) in Cluster A (lowest performance in most tests), 557 (55.9%) in Cluster B, and 334 (33.5%) in Cluster C (highest performance in most tests). The odds of multiply exposed children belonging to Cluster A was 2.83 (95% CI: 1.49-5.35; P=0.001) compared with belonging to Cluster B; there was no other significant association between exposure status and cluster membership. CONCLUSIONS: Multiple, but not single, exposures to procedures requiring general anaesthesia before age 3 yr are associated with a specific pattern of deficits in neuropsychological tests. Factors predicting which children develop the most pronounced deficits remain unknown.

Performance on the Operant Test Battery in young children exposed to procedures requiring general anaesthesia: the MASK study.

BACKGROUND: It is not known whether the neurotoxicity produced by anaesthetics administered to young animals can also occur in children. Exposure of infant macaques to ketamine impairs performance in selected domains of the Operant Test Battery (OTB), which can also be administered to children. This study determined whether a similar pattern of results on the OTB is found in children exposed to procedures requiring general anaesthesia before age 3 yr. METHODS: We analysed data from the Mayo Anesthesia Safety in Kids (MASK) study, in which unexposed, singly-exposed, and multiply-exposed children born in Olmsted County, MN, USA, from 1994 to 2007 were sampled using a propensity-guided approach and prospectively underwent OTB testing at ages 8-12 or 15-20 yr, using five tasks that generated 15 OTB test scores. RESULTS: In primary analysis, none of the OTB test scores depended upon anaesthesia exposure status when corrected for multiple comparisons. Cluster analysis identified four clusters of subjects, with cluster membership determined by relative performance on the OTB tasks. There was no evidence of association between exposure status and cluster membership. Exploratory factor analysis showed that the OTB scores loaded onto four factors. The score for one factor was significantly less in multiply-exposed children (mean standardised difference -0.28 [95% confidence interval, -0.55 to -0.01; P=0.04]), but significance did not survive a sensitivity analysis accounting for outlying values. CONCLUSIONS: These findings provide little evidence to support the hypothesis that children exposed to procedures requiring anaesthesia show deficits on OTB tasks that are similar to those observed in non-human primates.

Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study.

BACKGROUND: Few studies of how exposure of children to anesthesia may affect neurodevelopment employ comprehensive neuropsychological assessments. This study tested the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia before age 3 yr is associated with adverse neurodevelopmental outcomes. METHODS: Unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8 to 12 or 15 to 20 yr. The primary outcome was the Full-Scale intelligence quotient standard score of the Wechsler Abbreviated Scale of Intelligence. Secondary outcomes included individual domains from a comprehensive neuropsychological assessment and parent reports. RESULTS: In total, 997 children completed testing (411, 380, and 206 unexposed, singly exposed, and multiply exposed, respectively). The primary outcome of intelligence quotient did not differ significantly according to exposure status; multiply exposed and singly exposed children scoring 1.3 points (95% CI, -3.8 to 1.2; P = 0.32) and 0.5 points (95% CI, -2.8 to 1.9; P = 0.70) lower than unexposed children, respectively. For secondary outcomes, processing speed and fine motor abilities were decreased in multiply but not singly exposed children; other domains did not differ. The parents of multiply exposed children reported increased problems related to executive function, behavior, and reading. CONCLUSIONS: Anesthesia exposure before age 3 yr was not associated with deficits in the primary outcome of general intelligence. Although secondary outcomes must be interpreted cautiously, they suggest the hypothesis that multiple, but not single, exposures are associated with a pattern of changes in specific neuropsychological domains that is associated with behavioral and learning difficulties.

Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort.

BACKGROUND: Utilization of general anesthesia in children has important policy, economic, and healthcare delivery implications, yet there is little information regarding the epidemiology of these procedures in the United States. AIMS: The primary objective of this study was to describe in a geographically defined population the incidence of procedures requiring general anesthesia up to the child's third birthday, and the patient characteristics associated with receiving these procedures. A secondary objective was to determine the proportion of children in the population who meet the risk criteria promulgated by the Food and Drug Administration (FDA). METHODS: A retrospective cohort of children born from 1994 to 2007 in Olmsted County, MN was established. Birth certificate information and receipt of general anesthesia before age 3 were collected. Proportional hazard regressions were performed to evaluate the association between characteristics of children and incidence of general anesthesia. RESULTS: Among the 20 922 children in the cohort, 3120 (14.9%) underwent at least 1 general anesthesia before age 3. In multivariate regression, factors independently associated with receiving at least 1 procedure included prematurity, male sex, lower birth weight, cesarean delivery, a non-Hispanic mother, and a White mother, controlling for multiple gestation, number of children previously born, age, education, and marital status of the mother. Seven hundred and twenty-three children (3.5%) had at least 1 subsequent procedure. Estimated gestational age <32 weeks and low birth weight were independently associated with receiving repeated anesthesia. Eight hundred and twenty children (3.9%) had a single prolonged exposure above 3 hours, multiple exposures prior to age 3, or both. CONCLUSION: Approximately 1 in 7 children were exposed to at least 1 episode of general anesthesia before age 3, and approximately 1 in 4 children who received general anesthesia fall within the high-risk category as defined by the recent FDA warning. The apparent disparities in surgical utilization related to race and ethnicity in this study population deserve further exploration.

American College of Surgeons Children's Surgery Verification Quality Improvement Program: What Anesthesiologists Need to Know Now.

A task force of pediatric surgical specialists with the support of The American College of Surgeons recently launched a verification program for pediatric surgery, the Children's Surgery Verification quality improvement program, with the goal of improving pediatric surgical, procedural, and perioperative care. Included in this program are specific standards for the delivery of pediatric anesthesia care across a variety of practice settings. We review the background, available evidence, requirements for verification, and verification process and its implications for the practice of pediatric anesthesia across the country. In addition, we have included a special roundtable interview of 3 recently Children's Surgery Verification-verified program directors to provide an up-to-date real-world perspective of this children's surgery quality improvement program.

Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort.

BACKGROUND: Exposure of young animals to general anesthesia causes neurodegeneration and lasting behavioral abnormalities; whether these findings translate to children remains unclear. This study used a population-based birth cohort to test the hypothesis that multiple, but not single, exposures to procedures requiring general anesthesia before age 3 yr are associated with adverse neurodevelopmental outcomes. METHODS: A retrospective study cohort was assembled from children born in Olmsted County, Minnesota, from 1996 to 2000 (inclusive). Propensity matching selected children exposed and not exposed to general anesthesia before age 3 yr. Outcomes ascertained via medical and school records included learning disabilities, attention-deficit/hyperactivity disorder, and group-administered ability and achievement tests. Analysis methods included proportional hazard regression models and mixed linear models. RESULTS: For the 116 multiply exposed, 457 singly exposed, and 463 unexposed children analyzed, multiple, but not single, exposures were associated with an increased frequency of both learning disabilities and attention-deficit/hyperactivity disorder (hazard ratio for learning disabilities = 2.17 [95% CI, 1.32 to 3.59], unexposed as reference). Multiple exposures were associated with decreases in both cognitive ability and academic achievement. Single exposures were associated with modest decreases in reading and language achievement but not cognitive ability. CONCLUSIONS: These findings in children anesthetized with modern techniques largely confirm those found in an older birth cohort and provide additional evidence that children with multiple exposures are more likely to develop adverse outcomes related to learning and attention. Although a robust association was observed, these data do not determine whether anesthesia per se is causal.

Anesthetic-Related Neurotoxicity and Neuroimaging in Children: A Call for Conversation.

Each year millions of young children undergo procedures requiring sedation or general anesthesia. An increasing proportion of the anesthetics used are provided to optimize diagnostic imaging studies such as magnetic resonance imaging. Concern regarding the neurotoxicity of sedatives and anesthetics has prompted the US Food and Drug Administration to change labeling of anesthetics and sedative agents warning against repeated or prolonged exposure in young children. This review aims to summarize the risk of anesthesia in children with an emphasis on anesthetic-related neurotoxicity, acknowledge the value of pediatric neuroimaging, and address this call for conversation.

The American College of Surgeons Children's Surgery Verification and Quality Improvement Program: implications for anesthesiologists.

PURPOSE OF REVIEW: The Task Force for Children's Surgical Care, an ad-hoc multidisciplinary group of invited leaders in pediatric perioperative medicine, was assembled in May 2012 to consider approaches to optimize delivery of children's surgical care in today's competitive national healthcare environment. Over the subsequent 3 years, with support from the American College of Surgeons (ACS) and Children's Hospital Association (CHA), the group established principles regarding perioperative resource standards, quality improvement and safety processes, data collection, and verification that were used to develop an ACS-sponsored Children's Surgery Verification and Quality Improvement Program (ACS CSV). RECENT FINDINGS: The voluntary ACS CSV was officially launched in January 2017 and more than 125 pediatric surgical programs have expressed interest in verification. ACS CSV-verified programs have specific requirements for pediatric anesthesia leadership, resources, and the availability of pediatric anesthesiologists or anesthesiologists with pediatric expertise to care for infants and young children. SUMMARY: The present review outlines the history of the ACS CSV, key elements of the program, and the standards specific to pediatric anesthesiology. As with the pediatric trauma programs initiated more than 40 years ago, this program has the potential to significantly improve surgical care for infants and children in the United States and Canada.

Summary of the Update Session on Clinical Neurotoxicity Studies.

During the Fifth Pediatric Anesthesia Neurodevelopmental Assessment Symposium, experts and stakeholders met to present and discuss recent advances made in the study of neurodevelopmental outcomes after exposure to anesthetic drugs in infants and children. This article summarizes the update of 5 ongoing clinical studies: General Anesthesia compared to Spinal Anesthesia, Toxicity of Remifentanil and Dexmedetomidine, Mayo Anesthesia Safety in Kids, the University of California San Francisco human cohort study, and Columbia University Medical Center Neonatal Magnetic Resonance Imaging study. The purpose of this summary is to discuss the contributions and limitations of these studies, how they fit into the published literature, and what questions remain to be answered.

Construction and Characterization of a Population-Based Cohort to Study the Association of Anesthesia Exposure with Neurodevelopmental Outcomes.

Exposure to general anesthesia at an early age has been associated with adverse neurodevelopmental outcomes in both animal and human studies, but some of these studies employed anesthetic agents that are no longer in clinical use. In this manuscript, we describe the methods used to construct a new population-based study cohort to study the association between early anesthetic exposure and subsequent neurodevelopmental outcomes. A birth cohort of all children born in Olmsted County, MN from January 1, 1996 to December 31, 2000 was identified. For each, school enrollment status in the Independent School District (ISD) 535 at age 5 or 6 and all episodes of anesthetic exposure before age 3 were identified. A study cohort was created by matching children enrolled in ISD 535 based on the propensity of receiving general anesthesia. Three analyses were performed to characterize the study cohort by comparing the birth and parental information, comorbidities, and socioeconomic status. The first analysis compared the characteristics of birth cohort children who were and were not enrolled in ISD 535. The second analysis evaluated the success of the propensity matching schemes in creating groups of children that were similar in measured characteristics except for anesthesia exposure. The third analysis compared the characteristics of children with anesthesia exposures who were and were not included in the final cohort based on propensity matching. Results of these analyses demonstrate only slight differences among the comparison groups, and therefore these are unlikely to compromise our future analysis of anesthetic exposure and neurodevelopmental outcomes.