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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Anesthetic neurotoxicity: what to tell the parents?

Over the past decade, numerous preclinical and retrospective human studies have reported that the provision of anesthetic and sedative agents to infants and children may be associated with adverse neurodevelopmental outcomes. These data have gained widespread attention from professional and regulatory agencies, including the public at large. As such, pediatric anesthesiologists are being increasingly questioned by parents about the risks of anesthetic agents on their children's neurocognitive development. To impart a framework from which anesthesiologists may address the apprehensions of parents who actively bring up this issue, we review the data supporting anesthetic neurotoxicity and discuss its strengths and limitations. As many parents are not yet aware and do not actively raise these concerns, we also discuss whether such a conversation should be undertaken as a part of the consent process.

Quality and safety in pediatric anesthesia.

Health care quality and value are leading issues in medicine today for patients, health care professionals, and policy makers. Outcome, safety, and service-the components of quality-have been used to define value when placed in the context of cost. Health care organizations and professionals are faced with the challenge of improving quality while reducing health care related costs to improve value. Measurement of quality is essential for assessing what is effective and what is not when working toward improving quality and value. However, there are few tools currently for assessing quality of care, and clinicians often lack the resources and skills required to conduct quality improvement work. In this article, we provide a brief review of quality improvement as a discipline and describe these efforts within pediatric anesthesiology.

Outcomes of general anesthesia for noncardiac surgery in a series of patients with Fontan palliation.

OBJECTIVES: To describe the experience of a single, tertiary care institution in the care of patients with Fontan physiology undergoing anesthesia for noncardiac surgery. BACKGROUND: The Fontan procedure was developed in 1971 to palliate patients with univentricular cardiac physiology leading to long-term survival of these patients, who may now present as adults for noncardiac surgery. METHODS: We retrospectively reviewed the medical records of Fontan patients 16 years and older who underwent general anesthesia for noncardiac surgery at Mayo Clinic in Rochester, Minnesota. Preoperative data, perioperative course, intraoperative and postoperative hemodynamic, pulmonary, cardiovascular, and renal complications were described. RESULTS: Thirty-nine general anesthetics were administered to 31 patients for noncardiac surgery after Fontan palliation. Perioperative complications occurred in 12 of the 39 (31%) noncardiac surgeries, and there was one postoperative death that occurred on day 13 after ventral hernia repair. The two patients who had complications that did not resolve (long-term dialysis and death) had ejection fractions well below the mean for the group (22% and 28%). CONCLUSION: It may be more appropriate for Fontan patients to undergo anesthesia for noncardiac surgery in a tertiary institution, particularly patients with an ejection fraction of <30%. Intraoperative arterial blood pressure monitoring and overnight admission are likely appropriate for most cases.

New technologies in pediatric anesthesia.

This article reviews potential pediatric applications of 3 new technologies. (1) Pulse oximetry-based hemoglobin determination: Hemoglobin determination using spectrophotometric methods recently has been introduced in adults with varied success. This non-invasive and continuous technology may avoid venipuncture and unnecessary transfusion in children undergoing surgery with major blood loss, premature infants undergoing unexpected and complicated emergency surgery, and children with chronic illness. (2) Continuous cardiac output monitoring: In adults, advanced hemodynamic monitoring such as continuous cardiac output monitoring has been associated with better surgical outcomes. Although it remains unknown whether similar results are applicable to children, current technology enables the monitoring of cardiac output non-invasively and continuously in pediatric patients. It may be important to integrate the data about cardiac output with other information to facilitate therapeutic interventions. (3) Anesthesia information management systems: Although perioperative electronic anesthesia information management systems are gaining popularity in operating rooms, their potential functions may not be fully appreciated. With advances in information technology, anesthesia information management systems may facilitate bedside clinical decisions, administrative needs, and research in the perioperative setting.

Perioperative outcomes of severely obese children undergoing tonsillectomy.

BACKGROUND: Sleep-disordered breathing, a common condition in obese children, is a frequent indication for tonsillectomy. OBJECTIVE: The purpose of this study was to examine the association between obesity and perioperative complications in children undergoing tonsillectomy. METHODS/MATERIALS: A sample of 100 severely obese children (body mass index for age [BMIA], ≥ 98 th percentile) between ages 2 and 18 years who underwent tonsillectomy at Mayo Clinic Rochester was randomly selected. Each severely obese child was age (± 2 years) and sex matched to two normal weight children (BMIA between 25th and 75th percentiles) undergoing tonsillectomy during the study period, and their medical records were reviewed. RESULTS: Severely obese children had a significantly higher incidence of comorbid conditions including respiratory disorders and severe systemic disorders or syndromes. Severely obese children had a higher frequency of perioperative airway complications (15.0% vs 2.0%). From posthoc analyses, severe obesity remained a significant risk factor for perioperative adverse events after adjusting for the presence of severe systemic disorders or syndromes (OR 8.8; 95% CI 2.8-27.5, P < 0.001) and also after adjusting for preoperative respiratory disorders (OR 7.7; 95% CI 2.5-24.3, P < 0.001). When children with planned admissions were excluded from the analysis, severe obesity was associated with an increased rate of unplanned hospital admission (OR 3.80, 95% CI 1.8-7.9, P < 0.001). CONCLUSIONS: Severe obesity in children undergoing tonsillectomy is independently associated with an increased risk of perioperative complications. It appears that both severe obesity and systemic comorbid condition contribute to higher proportions of inpatient tonsillectomies performed in our institution.

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.

Neuraxial labor analgesia for vaginal delivery and its effects on childhood learning disabilities.

BACKGROUND: In prior work, children born to mothers who received neuraxial anesthesia for cesarean delivery had a lower incidence of subsequent learning disabilities compared with vaginal delivery. The authors speculated that neuraxial anesthesia may reduce stress responses to delivery, which could affect subsequent neurodevelopmental outcomes. To further explore this possibility, we examined the association between the use of neuraxial labor analgesia and development of childhood learning disabilities in a population-based birth cohort of children delivered vaginally. METHODS: The educational and medical records of all children born to mothers residing in the area of 5 townships of Olmsted County, Minnesota from 1976 to 1982 and remaining in the community at age 5 years were reviewed to identify those with learning disabilities. Cox proportional hazards regression was used to compare the incidence of learning disabilities between children delivered vaginally with and without neuraxial labor analgesia, including analyses adjusted for factors of either potential clinical relevance or that differed between the 2 groups in univariate analysis. RESULTS: Of the study cohort, 4684 mothers delivered children vaginally, with 1495 receiving neuraxial labor analgesia. The presence of childhood learning disabilities in the cohort was not associated with use of labor neuraxial analgesia (adjusted hazard ratio, 1.05; 95%confidence interval, 0.85-1.31; P = 0.63). CONCLUSION: The use of neuraxial analgesia during labor and vaginal delivery was not independently associated with learning disabilities diagnosed before age 19 years. Future studies are needed to evaluate potential mechanisms of the previous finding indicating that the incidence of learning disabilities is lower in children born to mothers via cesarean delivery under neuraxial anesthesia compared with vaginal delivery.