Sedation Research in Critically Ill Pediatric Patients: Proposals for Future Study Design From the Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research IV Workshop.

OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.

Children with Congenital Heart Disease Show Increased Behavioral Problems Compared to Healthy Peers: A Systematic Review and Meta-Analysis.

Millions of children and adults are living with congenital heart disease (CHD). Their risk for behavioral problems has not been the subject of a meta-analysis. We performed a systematic review and meta-analysis of measures of behavioral problems in people born with CHD compared to peers without CHD. We searched Pubmed, CINAHL, Embase, PsycInfo, and the Cochrane Library from January 1, 1986 to November 15, 2021. We included studies that reported a measure of behavioral problems in patients with CHD in children and adults older than 3 years of age. We screened 26,343 search results, and 24 studies met inclusion criteria. The quality of evidence was generally low. Subjects with CHD had a small increase in internalizing problems [standardized mean difference (SMD): 0.198, p = 0.02] and total behavior problems (SMD: 0.287, p = 0.013), but no difference in externalizing behavioral problems. There was significant heterogeneity in all three domains of behavior problems analyzed, and it could not be explained by variables such as age, severity, assessor, or assessment tool. There are small increases in parent- and self-reported overall behavioral problems and internalizing problems in patients with CHD compared to healthy controls. Wide confidence intervals in the meta-analyses leave open the possibility that certain factors may increase the risk of behavioral problems in this group, and future studies with important attention paid to potential confounders may help identify risk factors.

Development of a preoperative risk score predicting allogeneic red blood cell transfusion in children undergoing spinal fusion.

BACKGROUND: Children undergoing spinal fusion often receive blood products. The goal of this study was to develop a preoperative score to help physicians identify those who are at risk of allogeneic red blood cell (RBC) transfusion. STUDY DESIGN AND METHODS: This retrospective study of children undergoing spinal fusion in the ACS-NSQIP Pediatric database (2016-2019) aimed at identifying risk factors associated with allogeneic RBC transfusion. Univariable logistic regression and multivariable logistic regression were performed using preoperative patient characteristics and aided in the creation of a simplified scoring system. RESULTS: Out of 13,929 total patients, 2990 (21.5%) were transfused. We created a risk score based on 10 independent predictors of transfusion: age, sex, race, weight < 3rd percentile, American Society of Anesthesiologists physical status classification, cardiac risk factors, hematologic disease, preoperative anemia, deformity type, and number of spinal levels to be fused. Patients in both the training and testing cohorts were assigned a score ranging from 0 (lowest risk) to 21 (highest risk). The developed transfusion risk score showed 77% accuracy in distinguishing patients who did not receive a transfusion during or soon after surgery (AUROC 0.7736 [95% CI, 0.7619-0.7852]) in the training cohort and 77% accuracy (AUROC 0.7732 [95% CI, 0.7554-0.7910]) in the testing cohort. DISCUSSION: Our score, based on routinely available preoperative data, accurately estimates the risk of allogeneic RBC transfusion in pediatric patients undergoing spinal fusion. Future studies will inform whether patient blood management interventions targeted to high-risk patients can help reduce the need for transfusion and improve outcomes.

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.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Ultrasound Evaluation of Gastric Emptying Time in Healthy Term Neonates after Formula Feeding.

BACKGROUND: The current American Society of Anesthesiologists fasting guideline for formula-fed infants in the periprocedural setting is 6 h. Prolonged fasting in very young infants is associated with an increased risk for hypoglycemia and dehydration as well as patient discomfort and patient/parental dissatisfaction. This study aimed to determine the time to gastric emptying in healthy neonates after formula feeding by serially evaluating the gastric antrum with ultrasound. The authors hypothesized that gastric emptying times in formula-fed neonates are significantly shorter than the current 6 h fasting recommendation. METHODS: After institutional review board approval and written informed parental consent, ultrasound examination was performed in healthy full-term neonates before and after formula feeding at 15-min intervals until return to baseline. Ultrasound images of the gastric antrum were measured to obtain cross-sectional areas, which were then used to estimate gastric antral volumes. RESULTS: Forty-six of 48 recruited neonates were included in the final analysis. Gastric emptying times ranged from 45 to 150 min and averaged 92.9 min (95% CI, 80.2 to 105.7 min; 99% CI, 76.0 to 109.8 min) in the overall study group. No significant differences were found in times to gastric emptying between male and female neonates (male: mean, 93.3 [95% CI, 82.4 to 104.2 min]; female: mean, 92.6 [95% CI, 82.0 to 103.2 min]; P = 0.930) or those delivered by vaginal versus cesarean routes (vaginal: mean, 93.9 [95% CI, 81.7 to 106.1 min]; cesarean: mean, 92.2 [95% CI, 82.5 to 101.9 min]; P = 0.819). CONCLUSIONS: These results demonstrate that gastric emptying times are substantially less than the current fasting guideline of 6 h for formula-fed, healthy term neonates.

Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis.

BACKGROUND: Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear. METHODS: PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses. RESULTS: Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0-3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7-3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9-3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08-2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23-2.30; P=0.001). CONCLUSIONS: Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence.

Executive functions in children with heart disease: a systematic review and meta-analysis.

CONTEXT: People with CHD are at increased risk for executive functioning deficits. Meta-analyses of these measures in CHD patients compared to healthy controls have not been reported. OBJECTIVE: To examine differences in executive functions in individuals with CHD compared to healthy controls. DATA SOURCES: We performed a systematic review of publications from 1 January, 1986 to 15 June, 2020 indexed in PubMed, CINAHL, EMBASE, PsycInfo, Web of Science, and the Cochrane Library. STUDY SELECTION: Inclusion criteria were (1) studies containing at least one executive function measure; (2) participants were over the age of three. DATA EXTRACTION: Data extraction and quality assessment were performed independently by two authors. We used a shifting unit-of-analysis approach and pooled data using a random effects model. RESULTS: The search yielded 61,217 results. Twenty-eight studies met criteria. A total of 7789 people with CHD were compared with 8187 healthy controls. We found the following standardised mean differences: -0.628 (-0.726, -0.531) for cognitive flexibility and set shifting, -0.469 (-0.606, -0.333) for inhibition, -0.369 (-0.466, -0.273) for working memory, -0.334 (-0.546, -0.121) for planning/problem solving, -0.361 (-0.576, -0.147) for summary measures, and -0.444 (-0.614, -0.274) for reporter-based measures (p < 0.001). LIMITATIONS: Our analysis consisted of cross-sectional and observational studies. We could not quantify the effect of collinearity. CONCLUSIONS: Individuals with CHD appear to have at least moderate deficits in executive functions. Given the growing population of people with CHD, more attention should be devoted to identifying executive dysfunction in this vulnerable group.

Long-term Healthcare Utilization by Medicaid Enrolled Children with Neonatal Abstinence Syndrome.

OBJECTIVE: To evaluate healthcare utilization in Medicaid enrolled children with neonatal abstinence syndrome (NAS) in the first 2 years of life. STUDY DESIGN: A retrospective, longitudinal cohort study evaluating Medicaid enrolled children born in New York (1999-2011) and Texas (1999-2010) was performed. Healthcare utilization, including inpatient days, emergency department and outpatient visits, and filled prescriptions in children after birth hospitalization was assessed. A tapered propensity-matching methodology was used, matching each child with NAS with 5 children without NAS, first on demographics, then on both demographics and clinical covariates (clinical diagnoses and congenital anomalies at birth). Poisson and negative binomial regression were used to calculate healthcare utilization ratios (HUR). RESULTS: In the first 2 years of life, children with NAS (n = 3799) had increased healthcare utilization with more inpatient days and emergency department visits than demographically similar children without NAS. This increased utilization however did not persist after matching on clinical covariates and performing multiple comparisons adjustment (inpatient days [HUR, 1.01; 95% CI, 0.88-1.16; P = .89], total emergency department visits [HUR, 1.06; 95% CI, 1.01-1.11; P = .02]). Children with NAS conversely had 9% fewer outpatient office visits (HUR, 0.91; 95% CI, 0.87-0.95; P < .0001). CONCLUSIONS: A diagnosis of NAS does not appear to be an independent predictor of increased healthcare utilization in the first 2 years of life. These results differ from some other published studies, but may suggest that the increased healthcare utilization observed in children with NAS is due to higher incidences of perinatal complications and congenital anomalies in children with prenatal drug exposures.

Standards for preclinical research and publications in developmental anaesthetic neurotoxicity: expert opinion statement from the SmartTots preclinical working group.

In March 2019, SmartTots, a public-private partnership between the US Food and Drug Administration and the International Anesthesia Research Society, hosted a meeting attended by research experts, anaesthesia journal editors, and government agency representatives to discuss the continued need for rigorous preclinical research and the importance of establishing reporting standards for the field of anaesthetic perinatal neurotoxicity. This group affirmed the importance of preclinical research in the field, and welcomed novel and mechanistic approaches to answer some of the field's largest questions. The attendees concluded that summarising the benefits and disadvantages of specific model systems, and providing guidance for reporting results, would be helpful for designing new experiments and interpreting results across laboratories. This expert opinion report is a summary of these discussions, and includes a focused review of current animal models and reporting standards for the field of perinatal anaesthetic neurotoxicity. This will serve as a practical guide and road map for novel and rigorous experimental work.

Outcomes from wake up safe, the pediatric anesthesia quality improvement initiative.

BACKGROUND: Wake Up Safe, a Patient Safety Organization founded by the Society for Pediatric Anesthesia, collects data on serious adverse events along with demographic data from all pediatric patients receiving anesthesia care at participating institutions. This report reviews all events occurring between 2010 and 2015 and focuses on common adverse events that are anesthesia-related. AIMS: Determine which adverse events were most common from 2010 to 2015 among participating Wake Up Safe institutions. Determine how many anesthesia-related events were deemed to be preventable. METHODS: This is a descriptive report. The Wake Up Safe registry data were queried on September 29, 2017. Institutions were included if they had complete demographic data and at least 5 adverse events per year reported. At that time, 19 out of 29 institutions had complete demographic data for events from 2010 to 2015. This study describes demographic data and adverse events from these nineteen institutions. Descriptive data were extracted, and event rate was calculated for each adverse event category. In events that were assessed as primarily related to anesthesia, further detailed analysis was performed. RESULTS: Of all reported adverse events (2544 events), the most common were cardiac arrests (646, 31.6%), respiratory complications (598, 29.2%), and medication events (345, 16.9%). Of all anesthesia-related events (612 events), medication events were the most common (239, 31.9%), followed by respiratory complications (181, 24.1%), and cardiac arrests (139, 18.5%). Overall, 85% of anesthesia-related serious adverse events were deemed somewhat or almost certainly preventable. CONCLUSIONS: The majority of anesthesia-related serious adverse events reported to the Wake Up Safe database are preventable. Medication events are the most common anesthesia-related adverse events. Innovations aimed at decreasing medication events may be the most impactful.

A Multivariable Model Predictive of Unplanned Postoperative Intubation in Infant Surgical Patients.

BACKGROUND: Unplanned postoperative intubation is an important quality indicator, and is associated with significantly increased mortality in children. Infant patients are more likely than older pediatric patients to experience unplanned postoperative intubation, yet the literature provides few characterizations of this outcome in our youngest patients. The objective of this study was to identify risk factors for unplanned postoperative intubation and to develop a scoring system to predict this complication in infants undergoing major surgical procedures. METHODS: In this retrospective cohort study, The National Surgical Quality Improvement Program-Pediatric database was surveyed for all infants who underwent noncardiac surgery between January 1, 2012 and December 31, 2015 (derivation cohort, n = 56,962) and between January 1 and December 31, 2016 (validation cohort, n = 20,559). Demographic and perioperative clinical characteristics were examined in association with our primary outcome of unplanned postoperative intubation within 30 days of surgery. Risk factors were analyzed in the derivation cohort (2012-2015 data) using multivariable logistic regression with stepwise selection. Parameters from the final model were used to create a scoring system for predicting unplanned postoperative intubation. Data from the validation cohort were utilized to assess the performance of the scoring system using the area under the receiver operating characteristic curve. RESULTS: In the derivation cohort, 2.2% of the infants experienced unplanned postoperative intubation within 30 days of surgery. Of the 14 risk factors identified in multivariable analysis, 10 (age, prematurity, American Society of Anesthesiologists physical status, inpatient status, operative time >120 minutes, cardiac disease, malignancy, hematologic disorder, oxygen supplementation, and nutritional support) were included in the final multivariable logistic regression model to create the risk score. The area under the receiver operating characteristic curve of the final model was 0.86 (95% CI, 0.85-0.87) for the derivation cohort and 0.83 (95% CI, 0.82-0.85) for the validation cohort. CONCLUSIONS: About 1 in 50 infants undergoing major surgical procedures experiences unplanned postoperative intubation. Our scoring system based on routinely collected perioperative assessment data can predict risk in infants with good accuracy. Further investigation should assess the clinical utility of the scoring system for risk stratification and improvement in perioperative care quality and patient outcomes.

Clinical Evidence for Any Effect of Anesthesia on the Developing Brain.

A recent U.S. Food and Drug Administration warning advised that prolonged or repeated exposure to general anesthetics may affect neurodevelopment in children. This warning is based on a wealth of preclinical animal studies and relatively few human studies. The human studies include a variety of different populations with several different outcome measures. Interpreting the results requires consideration of the outcome used, the power of the study, the length of exposure and the efforts to reduce the confounding effects of comorbidity and surgery. Most, but not all, of the large population-based studies find evidence for associations between surgery in early childhood and slightly worse subsequent academic achievement or increased risk for later diagnosis of a behavioral disability. In several studies, the amount of added risk is very small; however, there is some evidence for a greater association with multiple exposures. These results may be consistent with the preclinical data, but the possibility of confounding means the positive associations can only be regarded as weak evidence for causation. Finally, there is strong evidence that brief exposure is not associated with any long term risk in humans.

Identification of perioperative pulmonary aspiration in children using quality assurance and hospital administrative billing data.

BACKGROUND: Perioperative aspiration is a rare but potentially devastating complication, occurring in 1-10 per 10 000 anesthetics based on studies of quality assurance databases. Quality assurance reporting is known to underestimate the incidence of adverse outcomes, but few large studies use supplementary data sources. This study aims to identify the incidence of and risk factors for perioperative aspiration in children using quality assurance data supplemented by administrative billing records, and to examine the utility of billing data as a supplementary data source. METHODS: Aspiration events for children receiving anesthesia at a tertiary care pediatric hospital between 2008 and 2014 were identified using (i) a perioperative quality assurance database and (ii) hospital administrative billing records with International Classification of Diseases, Ninth Revision Clinical Modification coded diagnoses of aspiration. Records were subject to review by pediatric anesthesiologists. Following identification of all aspiration events, the incidence of perioperative aspiration was calculated and risk factors were assessed. RESULTS: 47 272 anesthetic cases were evaluated over 7 years. The quality assurance database identified 20 cases of perioperative aspiration occurring in surgical inpatients, same-day admissions, and outpatients. Using hospital administrative data (which excludes outpatients with shorter than a 24-hour stay), 9 cases of perioperative aspiration were identified of which 6 had not been found through quality assurance data. Overall, International Classification of Diseases, Ninth Revision coding demonstrated a positive predictive value of 94.5% for any aspiration event; however, positive predictive value was <4% for perioperative aspiration. A total incidence of 5.5 perioperative aspirations per 10 000 (95% CI: 3.7-8.0 per 10 000) anesthetics was found. CONCLUSION: Quality assurance data offer an efficient way to measure the incidence of rare events, but may underestimate perioperative complications. International Classification of Diseases, Ninth Revision codes for aspiration used as a secondary data source were nonspecific for perioperative aspiration, but when combined with record review yielded a 30% increase in identified cases of aspiration over quality assurance data alone. The use of administrative data therefore holds potential for supplementing quality assurance studies of rare complications.

Anesthesia and the developing brain: A way forward for laboratory and clinical research.

All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long-term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well-designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare-related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered.

Age at Exposure to Surgery and Anesthesia in Children and Association With Mental Disorder Diagnosis.

BACKGROUND: Animals exposed to anesthetics during specific age periods of brain development experience neurotoxicity, with neurodevelopmental changes subsequently observed during adulthood. The corresponding vulnerable age in children, however, is unknown. METHODS: An observational cohort study was performed using a longitudinal dataset constructed by linking individual-level Medicaid claims from Texas and New York from 1999 to 2010. This dataset was evaluated to determine whether the timing of exposure to anesthesia ≤5 years of age for a single common procedure (pyloromyotomy, inguinal hernia, circumcision outside the perinatal period, or tonsillectomy and/or adenoidectomy) is associated with increased subsequent risk of diagnoses for any mental disorder, or specifically developmental delay (DD) such as reading and language disorders, and attention deficit hyperactivity disorder (ADHD). Exposure to anesthesia and surgery was evaluated in 11 separate age at exposure categories: ≤28 days old, >28 days and ≤6 months, >6 months and ≤1 year, and 6-month age intervals between >1 year old and ≤5 years old. For each exposed child, 5 children matched on propensity score calculated using sociodemographic and clinical covariates were selected for comparison. Cox proportional hazards models were used to measure the hazard ratio of a mental disorder diagnosis associated with exposure to surgery and anesthesia. RESULTS: A total of 38,493 children with a single exposure and 192,465 propensity score-matched children unexposed before 5 years of age were included in the analysis. Increased risk of mental disorder diagnosis was observed at all ages at exposure with an overall hazard ratio of 1.26 (95% confidence interval [CI], 1.22-1.30), which did not vary significantly with the timing of exposure. Analysis of DD and ADHD showed similar results, with elevated hazard ratios distributed evenly across all ages, and overall hazard ratios of 1.26 (95% CI, 1.20-1.32) for DD and 1.31 (95% CI, 1.25-1.37) for ADHD. CONCLUSIONS: Children who undergo minor surgery requiring anesthesia under age 5 have a small but statistically significant increased risk of mental disorder diagnoses and DD and ADHD diagnoses, but the timing of the surgical procedure does not alter the elevated risks. Based on these findings, there is little support for the concept of delaying a minor procedure to reduce long-term neurodevelopmental risks of anesthesia in children. In evaluating the influence of age at exposure, the types of procedures included may need to be considered, as some procedures are associated with specific comorbid conditions and are only performed at certain ages.

Differences in intraoperative hemodynamics between spinal and general anesthesia in infants undergoing pyloromyotomy.

BACKGROUND: Hypotension and bradycardia are known side effects of spinal anesthesia in pregnant women undergoing cesarean section and adults undergoing other surgical procedures. Whether children experience similar hemodynamic changes is unclear. AIMS: The purpose of this study is to evaluate hemodynamic effects of spinal anesthesia compared to general anesthesia in a cohort of healthy infants. METHODS: The University of Vermont Medical Center almost exclusively used spinal anesthesia for infant pyloromyotomy surgery between 2008 and 2013, while Columbia University Medical Center relied on general anesthesia. The primary outcome assessed was the percentage change in intraoperative heart rate and blood pressure (systolic [SBP] and mean [MAP] blood pressure) from baseline. Analysis was performed using t-tests for continuous variables, followed by linear regression to account for differences in demographic and clinical covariates. RESULTS: The study sample consisted of 51 infants with spinal anesthesia at the University of Vermont and 52 infants with general anesthesia at Columbia University. The decrease from baseline for mean intraoperative SBP was -8.2 ± 16.8% for spinal anesthesia and -24.2 ± 17.2% for general anesthesia (difference between means: 16.2% [95% confidence interval (CI), 9.5-22.9]), while the decrease from baseline for mean intraoperative MAP was -16.3 ± 19.9% for spinal anesthesia and -24.6 ± 19.3% for general anesthesia (difference between means: 8.4% [95% CI, 0.8-16]). Spinal anesthesia patients also had smaller drops in minimum intraoperative MAP and SBP. These blood pressure differences persisted even after adjusting for covariates. No differences in heart rate were seen between spinal and general anesthesia. DISCUSSION: Our findings show that spinal anesthesia performed in healthy infants undergoing pyloromyotomy results in reduced intraoperative blood pressure changes from baseline, significantly higher blood pressure readings, and no increased bradycardia compared to general anesthesia. Further research is needed to assess whether any clinical impact of these hemodynamic differences between spinal and general anesthesia exists.

Intrauterine growth restriction impairs right ventricular response to hypoxia in adult male rats.

BACKGROUND: Intrauterine growth restriction (IUGR) predisposes to cardiovascular diseases in adulthood. The mechanisms of this phenomenon remain cryptic. We hypothesized that heart mitochondria in IUGR-born adult rats are more sensitive to acute hypoxia which translates into dysfunctional cardiac response to hypoxic stress. METHODS: Adult IUGR-born male rats (the offspring of dams fed with calories-restricted diet during pregnancy) were exposed to acute hypoxic stress with echocardiographic assessment of cardiac function. In parallel, mitochondrial respiration in organelles isolated from left ventricle (LV) and right ventricle (RV) was tested in normoxic and anoxic conditions. The extent of post-anoxic inhibition of mitochondrial respiration and cardiac function was compared with controls, non-IUGR rats. RESULTS: Compared with controls, in the IUGR rats hypoxia significantly reduced only RV contractility, evidenced by decreased fractional shortening, functional area of contraction, and tricuspid annular plane systolic excursion. In isolated mitochondria, anoxic challenge inhibited respiratory chain in both groups of rats. However, compared with controls, the extent of anoxic mitochondrial depression was significantly greater in IUGR-born rats, but only in the organelles isolated from RV. CONCLUSIONS: In adult IUGR-born rats, mitochondria from RV are hypersensitive to oxygen deprivation and this translates into maladaptive RV cardiac response to acute hypoxia.

Neurotoxicity, general anesthesia in young children, and a survey of current pediatric anesthesia practice at US teaching institutions.

BACKGROUND: Recent articles in both scholarly journals and the lay press about the topic of anesthetic related neurotoxicity have increased the awareness and discussion of this topic with parents and other pediatric medical specialties (i.e., surgeons, radiologists, and pediatricians). AIM: The purpose of the present study was to survey how a subset of pediatric anesthesia departments in the US have responded to the issue of anesthetic related neurotoxicity in terms of clinical practice, training and communication with other medical specialties, and the frequency and timing of discussions with families. METHODS: A survey consisting of 22 questions was sent to PALC (Pediatric Anesthesia Leadership Council) & PAPDA (Pediatric Anesthesia Program Directors Association) via SurveyMonkey. The survey was divided into sections on Anesthesia Faculty/Trainees, Parents and Non-Anesthesia Providers. Responses to the survey were solicited via email to PALC and PAPDA, and then followed up with reminders to individual emails using the mailing lists of both organizations. RESULTS: The results of this survey demonstrate that pediatric anesthesia programs around the US do not have a consistent approach in managing the topic of anesthesia-related neurotoxicity with pediatric anesthesiologists, anesthesiology residents, pediatric anesthesiology fellows and their non-anesthesia medical and surgical colleagues, as well as the discussion of this topic with parents. CONCLUSION: A significant need exists to provide information to other pediatric professionals and parents. A consistent message from all providers that includes what is known, and indeed more importantly what is not known may be a useful approach.

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood.

IMPORTANCE: Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. OBJECTIVE: To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. DESIGN, SETTING, AND PARTICIPANTS: Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. EXPOSURES: A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. MAIN OUTCOMES AND MEASURES: The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. RESULTS: Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = -0.2 (95% CI, -2.6 to 2.9); performance = 0.5 (95% CI, -2.7 to 3.7); and verbal = -0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. CONCLUSIONS AND RELEVANCE: Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.