Concerns persist regarding the potential long-term effects of general anaesthesia on brain development in children. This narrative review summarises recent preclinical and clinical evidence (2019-25) and updates consensus messages. Preclinical studies show that commonly used anaesthetic agents can interfere with neurodevelopmental processes during vulnerable developmental periods. Clinical evidence is less clear. Randomised trials indicate that a single, short exposure in infancy is not associated with measurable impairment in cognitive outcomes, whereas observational studies report mixed findings. Several large population-based studies consistently identified a small, increased risk of attention-deficit hyperactivity disorder following early exposure to general anaesthesia. Emerging evidence also suggests modifications in visual development and processing, including preferential processing of global visual information, although these findings remain preliminary. Interpretation is limited by confounding related to surgery, comorbidity, and environmental factors. Communication with families should emphasise acknowledgment of parental concerns, individualised anaesthetic care, physiological stability, and that necessary procedures should not be delayed because of theoretical neurodevelopmental risks.

Postmenstrual age (PMA) is the major risk factor for postanesthesia apnea. The authors hypothesized that modern anesthesia may reduce the at-risk PMA cutoff threshold. The aim of this individual participant data meta-analysis was to identify the PMA above which postanesthesia apnea risk is less than 1%. Individual participant data from 12 prospective studies undergoing open inguinal herniorrhaphy were analyzed. A total of 132 of 751 (17.6%) former preterm infants experienced postanesthesia apnea. The data indicate that the PMA cutoff at which the risk of postanesthesia apnea was approximately 10%, approximately 5%, and less than 1% was 53 weeks, 57 weeks, and 65 weeks, respectively, after general anesthesia and approximately 38 weeks, 40 weeks, and 45 weeks, respectively, after neuraxial anesthesia. Anemia was a risk factor only for infants more than 48 weeks PMA. Postanesthesia apnea onset was earlier and odds for occurrence were higher for general anesthesia without (odds ratio, 6; P = 0.008) and with caudal block (odds ratio, 2.94; P = 0.012) compared to neuraxial anesthesia. Anesthetic technique has important implications; neuraxial anesthesia appears to reduce the at-risk PMA for postanesthesia apnea compared with general anesthesia.

BACKGROUND:The general anaesthesia or awake-regional anaesthesia in infancy (GAS) trial demonstrated evidence that most neurodevelopmental outcomes at 2 and 5 yr of age in infants who received a single general anesthetic for elective inguinal herniorrhaphy were clinically equivalent when compared to infants who did not receive general anesthesia. More than 20% of the children in the trial had at least one subsequent anesthetic exposure after their initial surgery. Using the GAS database, this study aimed to address whether multiple (two or more) general anesthetic exposures compared to one or no general anesthetic exposure in early childhood were associated with worse neurodevelopmental outcomes at 5 yr. METHODS:Children with multiple general anesthetic exposures and children with one or no general anesthetic exposure were identified from the GAS database. The primary outcome was the full-scale intelligence quotient on the Wechsler Preschool and Primary Scale of Intelligence (third edition) at 5 yr of age. Secondary outcomes included neurocognitive tests addressing all major developmental domains and caregiver-reported questionnaires assessing emotional and behavioral problems. RESULTS:Complete assessment was available from a total of 90 children in the multiple general anesthetic group and 141 children in the no or one general anesthetic group. Compared with children with a single or no general anesthetic exposure, multiply exposed children scored on average almost 6 points lower (mean, -5.8; 95% CI, -10.2 to -1.4; P = 0.011) in the Wechsler Preschool and Primary Scale of Intelligence full-scale intelligence quotient. They also demonstrated lower verbal and performance IQ scores and more emotional, behavioral, and executive function difficulties. However, significant residual confounding cannot be excluded from the results due to the observational nature of this study. CONCLUSIONS:Multiple general anesthetic exposures before 5 yr of age were associated with reduced performance in general intelligence score and some domains of neurodevelopmental assessments. The clinical significance of this study's results must be cautiously interpreted in light of several sources of limitations including small sample size and unadjusted residual confounding. This study illustrates the limitations of trial data sets that may not be fit for the purpose for the secondary analysis.

Background: The Trial Remifentanil DEXmedetomidine (TREX) trial aimed to determine whether, in children less than 2 yr old, low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia is superior to standard-dose sevoflurane anesthesia in terms of global cognitive function at 3 yr of age. The aim of the current secondary analyses was to compare incidence of intraoperative hypotension and bradycardia, postoperative pain, time to recovery, need for treatment of intraoperative hypotension and bradycardia, incidence of light anesthesia and need for treatment, need for postoperative pain medications, and morbidity and mortality outcomes at 5 days between the two arms. Methods: This phase III randomized active controlled, parallel group, assessor blinded, multicenter, superiority trial was performed in 20 centers in Australia, Italy, and the United States. A total of 455 infants less than 2 yr of age expected to undergo general anesthesia for at least 2 h were enrolled. They were randomized between low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia and standard-dose sevoflurane. The short-term perioperative outcomes noted above were compared between these two groups. Results: There was less hypotension (risk difference, -11.6%; 95% CI, -18.9 to -4.3%) and more bradycardia (risk difference, 18.2%; 95% CI, 8.8 to 27.7%) in the low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia compared to the standard-dose sevoflurane arm. There were more patients with episodes of light anesthesia (89 vs. 4), and protocol abandonments (1 vs. 0) in the low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia arm. Time from eye opening to postanesthesia care unit discharge was similar in both arms, as were morbidity and mortality. One patient in each arm suffered a life-threatening event, but neither suffered long-term sequelae. Conclusions: These early postoperative results suggest that in children less than 2 yr of age receiving greater than 2 h of general anesthesia, the low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia technique and the standard sevoflurane anesthesia technique are broadly clinically similar, with no clear evidence to support choosing one technique over the other.

From the Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts. Accepted for publication November 3, 2022. Funding: None. The authors declare no conflicts of interest. Address correspondence to Sulpicio G. Soriano, MD, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. Address e-mail to [email protected].

Background: The volatile anaesthetic sevoflurane induces time (single or multiple exposures)-dependent effects on tau phosphorylation and cognitive function in young mice. The underlying mechanism for this remains largely undetermined.Methods: Mice received 3% sevoflurane for 0.5 h or 2 h daily for 3 days on postnatal day (P) 6, 9, and 12. Another group of mice received 3% sevoflurane for 0.5 h or 1.5 h (3 x 0.5) on P6. We investigated effects of sevoflurane anaesthesia on tau phosphorylation on P6 or P12 mice, on cognitive function from P31 to P37, and on protein interactions, using in vivo studies, in vitro phosphorylation assays, and nanobeam single-molecule level interactions in vitro.Results: An initial sevoflurane exposure induced CaMKIIa phosphorylation (132 [11]% vs 100 [6]%, P<0.01), leading to tau phosphorylation at serine 262 (164 [7]% vs 100 [26]%, P<0.01) and tau detachment from microtubules. Subsequent exposures to the sevoflurane induced GSK3I3 activation, which phosphorylated detached or free tau (tau phosphorylated at serine 262) at serine 202 and threonine 205, resulting in cognitive impairment in young mice. In vitro phosphorylation assays also demonstrated sequential tau phosphorylation. Nanobeam analysis of molecular interactions showed different interactions between tau or free tau and CaMKIIa or GSK3I3, and between tau and tubulin at a single-molecule level.Conclusions: Multiple exposures to sevoflurane can induce sequential tau phosphorylation, leading to cognitive impairment in young mice, highlighting the need to investigate the underlying mechanisms of anaesthesia-induced tau phosphorylation in developing brain.

We present a case of a 12-year-old female with a history of infantile spasms who developed a propofol-associated acute dystonic reaction after emergence from general anesthesia for foot surgery. Uniquely, the patient's postoperative symptoms of an acute dystonic reaction were refractory to standard treatment with anticholinergics but were successfully treated with corticosteroids. The absence of any dystonic symptoms following subsequent foot surgery under general anesthesia without propofol supported a propofol-associated etiology. This case may contribute to a better understanding of the underlying mechanisms of propofol-associated acute dystonic reactions and adds a possible new treatment option.

( Anesthesiology . 2022;136:500–512. doi: 10.1097/ALN.0000000000004116) Decades ago, some studies showed early exposure to anesthetics increased the risk of altered neurodevelopment while others showed no such association. The debate about any association between anesthesia and neurodevelopment continues today. As these questions affect millions of children who undergo anesthetic-requiring procedures, this report aimed to provide current preclinical and clinical evidence, unanswered questions, and research suggestions going 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.

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.

One of the missions of the Food and Drug Administration (Silver Spring, Maryland) is to protect the public health by assuring the safety, efficacy, and security of human drugs.1 According to Food and Drug Administration guidance, new drugs can be approved as long as they show efficacy compared to placebo, even if there are already drugs approved and available that have been deemed effective.2 Exparel (Pacira Biosciences, Inc., USA), an extended release liposomal formulation of bupivacaine, first approved by the Food and Drug Administration in 2011 for surgical site infiltration, was approved under these circumstances. In this issue, two articles review 10 yr of research on the clinical effectiveness of liposomal bupivacaine. Ilfeld et al.3 provide an extensive narrative review of published randomized controlled trials, and Hussain et al.4 conducted a systemic review and meta-analysis of the clinical effectiveness of liposomal versus nonliposomal bupivacaine for peripheral nerve blocks.The narrative review by Ilfeld et al. included 76 randomized controlled trials. Importantly, they were evaluated using the Cochrane Risk of Bias Version 2 tool. This tool consists of five domains: bias from the randomizing process, bias due to deviations from intended intervention, bias due to missing outcome data, bias in measurement of outcome, and bias in selection of reported results. It does not measure the conduct of a trial. A summary bias judgment can be either “low” or “high” risk of bias, or can express “some concerns,” and a high risk summary judgment generally indicates a finding of high risk in at least one of the domains.5 The authors found that 35 to 40% of randomized controlled trials reviewed had evidence of high risk or some concerns for bias. The chief sources of bias included lack of trial registration, registration after enrollment, failure to define the primary outcome measure, and problems with definition (e.g., discrepancy between registry and published article). Minimization of bias in randomized controlled trials is important to prevent data distortion and erroneous conclusions. The Cochrane Risk of Bias tool does not measure conflicts of interest by industry funding. Almost half of the studies in this review reported either direct funding or financial support for the authors by the manufacturer of liposomal bupivacaine. Not surprisingly, liposomal bupivacaine was found to be superior to comparators in 46% of these conflicted trials but was found to be superior in only 11% of the nonconflicted trials.The primary outcome in these 76 trials varied and was not always designated. There were two types of primary outcome measures used: postoperative pain scales such as the visual analogue scale scores and numeric rating scales scores, or the mean morphine equivalents administered postoperatively to “rescue” the patient from pain. Some studies reported mean values, and others reported area under the curve values.The first 12 studies reviewed compared liposomal bupivacaine surgical site infiltration to placebo. Seven found no statistical difference between liposomal bupivacaine and placebo, and of these, 88% were deemed at low risk for bias. The five that did show statistical differences were all rated with high risk for bias. Thirty-six of the randomized controlled trials compared surgical site infiltration of liposomal bupivacaine to surgical site infiltration of bupivacaine, ropivacaine, or lidocaine. Twenty-seven of these comparisons used a maximum dose of liposomal bupivacaine of 266 mg but used a smaller dose of regular bupivacaine or ropivacaine, possibly biasing the studies toward results favoring liposomal bupivacaine. Only six of the 36 studies of comparing surgical site infiltration with liposomal bupivacaine with nonliposomal local anesthetic infiltration found the liposomal preparation to be superior. Five of these six studies were judged to have high or concerning risk for bias. In five of the six studies, the active comparator dose of bupivacaine was much lower than the liposomal bupivacaine dose, demonstrating that more bupivacaine works better than less bupivacaine. Twelve studies compared liposomal bupivacaine for surgical infiltration with a peripheral nerve block administered with either nonliposomal bupivacaine or ropivacaine. The final group of 16 studies evaluated liposomal bupivacaine for a nerve block or epidural injection compared to placebo or active comparators, nonliposomal bupivacaine, or intrathecal hydromorphone, using the similar outcome measures to all the previous trials. Of these last 28 trials reviewed, 43% showed superiority of liposomal bupivacaine; 82% showed high risk or some concerns for bias. The authors concluded, “Whether introduced by surgical infiltration or as part of a peripheral nerve block, the preponderance of current evidence fails to support the routine use of liposomal bupivacaine over standard local anesthetics when treating postoperative pain.”The systematic review and meta-analysis by Hussain et al. of the clinical effectiveness of liposomal versus nonliposomal bupivacaine for peripheral nerve blocks evaluated the primary outcome of the 24- to 72-h difference in the weighted mean area under the curve rest pain scores between patients receiving perineural analgesia inclusive of liposomal bupivacaine versus nonliposomal local anesthetics. The authors chose this time frame for the primary outcome measure because liposomal bupivacaine is promoted to improve the duration and quality of analgesia beyond the first 24 h.4 A variety of secondary outcomes relating to postoperative pain rating scores and opioid rescues were also evaluated during the postoperative period of 0 to 72 h. Nine trials were included in this meta-analysis. The authors found that the mean difference (95% CI) in area under the curve of rest pain was found to be 1.0 cm/h (0.5 to 1.6; P = 0.003) in favor of liposomal bupivacaine, but this difference failed to meet the predefined threshold for clinical significance (i.e., 2.0 cm/h; P < 0.001). Liposomal bupivacaine was similar to nonliposomal bupivacaine for all other analgesic and functional outcomes. The authors concluded that liposomal bupivacaine used perineurally in peripheral nerve blocks provides a clinically unimportant improvement in the area under the curve of postoperative pain scores compared to nonliposomal bupivacaine.The results of these two articles should not come as a surprise in light of the early studies performed for the regulatory approval of liposomal bupivacaine. In 2006, SkyePharma, later known as Pacira Pharmaceuticals and then Pacira Biosciences, collectively referred to here as Pacira Biosciences, submitted an New Drug Application application to the Food and Drug Administration for Exparel brand liposomal bupivacaine for an indication of relief of postoperative surgical pain, administered as wound infiltration.6 For this indication, Pacira submitted five phase 2 active comparator-controlled studies and three phase 3 active comparator-controlled studies using nonliposomal bupivacaine as the comparator.6 None of these eight studies showed clinical or statistical difference between the two formulations.Unable to demonstrate a benefit over nonliposomal bupivacaine, in 2009, the sponsor submitted two phase 3 placebo-controlled clinical trials showing efficacy of liposomal bupivacaine against placebo.6 As allowed by regulation, despite no greater efficacy of liposomal bupivacaine than nonliposomal bupivacaine, the Food and Drug Administration in 2011 approved liposomal bupivacaine for surgical site infiltration to relieve postoperative pain for hemorrhoidectomy and bunionectomy. For this initial approval, the Food and Drug Administration deemed it not necessary for an advisory committee to meet.7In 2014, Pacira submitted a supplemental New Drug Application application for approval of liposomal bupivacaine for an additional indication of postsurgical analgesia via nerve block, for which they submitted data from two new studies. The first investigated intercostal nerve blocks and found that liposomal bupivacaine was not superior to placebo, based on no differences in area under the curve analysis for pain intensity at rest using a numerical rating scale-R over 72 h. The second investigated femoral nerve blocks and found that liposomal bupivacaine at a dose of 266 mg was superior to placebo for pain relief, based on a primary outcome measure of area under the curve analysis of Numeric Rating Scale-Rest through 72 h but not superior on its secondary outcome measure of time to first opioid rescue. This supplemental New Drug Application was not approved in the first review cycle. In 2017, Pacira submitted two new multicenter, randomized, double-blind, and placebo-controlled nerve block studies.8,9 The first evaluated the efficacy of liposomal bupivacaine for postsurgical analgesia via femoral nerve block in patients undergoing total knee arthroplasty. The second evaluated liposomal bupivacaine for postsurgical analgesia via ultrasound-guided brachial plexus nerve blocks by either supraclavicular or interscalene approach in patients undergoing shoulder surgery. Out of these four studies, both the two in 2014 and the two in 2017, the brachial plexus nerve block study was the only one that met both the primary efficacy endpoint of improved area under the curve estimates of pain relief for the first 48 to 72 h after surgery and decreased opioid rescues.The Food and Drug Administration Anesthetic and Drug Products Advisory Committee met in 2018 to review the supplemental New Drug Application request to approve liposomal bupivacaine for the new indication of regional nerve blocks.10,11 This advisory committee consisted of 10 members with expertise in anesthesiology, pain medicine, pharmacology, or biostatistics, as well as a consumer and industry representative. Concerns raised by this committee included the lack of active comparator groups in the submitted studies, a lack of safety studies, and the lack of evidence for opioid sparing. Most of the voting advisory committee members voted six to four against expanding the indication for liposomal bupivacaine. In 2018, the Food and Drug Administration approved Exparel for “…use as an interscalene brachial plexus nerve block to produce post-surgical regional analgesia following shoulder surgery in adults.”12To summarize, both the review by Ilfeld et al. and the meta-analysis by Hussain et al. concluded that liposomal bupivacaine did not show clinical superiority over existing, active comparators, nonliposomal bupivacaine or ropivacaine. For the indication for infiltration, the studies submitted by Pacira Biosciences did not demonstrate superiority of liposomal bupivacaine compared to these same active comparators. For the indication of peripheral nerve block, they submitted only placebo studies. Although demonstrating efficacy of a new agent is simplest using a randomized placebo-controlled trial design, this design gives no information about the efficacy of a new agent compared to existing agents. Trials that have an active comparator arm as well as a placebo arm can determine efficacy as well as give information about efficacy vis-à-vis existing, effective drugs.Why is all of this important? New drugs can be very financially rewarding for pharmaceutical companies.13 Once Exparel was approved, Pacira Biosciences began an aggressive and powerful marketing strategy. Between 2013 and 2019, they paid $25.8 million to more than 27,000 physicians for a variety of services including compensation for being a speaker or faculty at nonaccredited educational events.14 Sales of liposomal bupivacaine increased during this time with the company reporting a 25% growth in 2019 over 2018 with full-year revenues of $421 million in 2019.15 The cost of a single dose of 266 mg of Exparel brand liposomal bupivacaine is about $334.16 Nonliposomal bupivacaine costs about $3 per dose. In this era of medical austerity, when the benefits and costs of expensive drugs are being considered, one would hope that newly approved expensive drugs would at least be an improvement over existing, inexpensive drugs.The author declares no competing interests. The author was the acting Chair for the Food and Drug Administration Anesthetic and Analgesic Drug Products Advisory Committee February 14 and 15, 2018, which advised on Pacira’s (Pacira Biosciences, Parsippany, New Jersey) sNDA application for expanded indication for Exparel for nerve blocks.

Background: High-volume centers for idiopathic scoliosis (IS) have difficulty in scheduling posterior spinal fusions (PSFs) due to operating room availability, particularly during school vacation. A solution is for 1 surgeon to perform 2 PSF cases back-to-back. This study aims to compare morning and afternoon PSF cases performed by the same surgeon for perioperative outcomes. Methods: A retrospective review of PSF cases for IS that occurred on the same day as another PSF by the same surgeon between January 2013 and December 2019 was conducted. Perioperative outcomes included surgical time, estimated blood loss, length of stay, and inpatient opioid consumption normalized by the patient’s weight. Postoperative outcomes included complications, revision rate, curve correction, and patient-reported outcomes using the Scoliosis Research Society-30. Results: A total of 95 patients (87% female), mean age 15.6 years, were analyzed, with 48 morning cases and 47 afternoon cases. The median follow-up was 1.9 years (range: 0.3 to 6.1 y). Tests for equivalency determined equivalence in median anesthesia and mean surgical duration (P=0.05). The groups had similar initial curve correction (P=0.43) and rate of complications at 90 days postoperative (2 in each group for a total of 4 complications). No significant differences were seen between Scoliosis Research Society-30 scores at 6 months or in those who have reached 2 years postoperative. Conclusions: Little literature exists on the safety of a surgeon performing 2 PSF cases in 1 day, particularly in regard to pain outcomes, 30- and 90-day complication rates, and quality of life measures. This study indicates that few differences in safety, pain, and quality of life outcomes may appear between morning and afternoon PSF cases. Level of Evidence: Level II.

There are compelling preclinical data that common general anesthetics cause increased neuroapoptosis in juvenile animals. Retrospective studies demonstrate that young children exposed to anesthesia have school difficulties, which could be caused by anesthetic neurotoxicity, perioperative hemodynamic and homeostatic instability, underlying morbidity, or the neuroinflammatory effects of surgical trauma. Unnecessary procedures should be avoided. Baseline measures of blood pressure are important in determining perioperative blood pressure goals. Inadvertent hypocapnia or moderate hypercapnia and hyperoxia or hypoxia should be avoided. Pediatric patients should be maintained in a normothermic, euglycemic state with neutral positioning. Improving outcomes of infants and children requires the collaboration of anesthesiologists, surgeons, pediatricians and neonatologists.

See Articles, p 723 and 734 Why do so many otherwise healthy children acquire neurological impairments after treatment for a serious illness? It is rare for us to see a chronically ill child who has had many surgical procedures who does not develop a neurological impairment. This observation has been corroborated in the literature.1 Therefore, the hypothesis that general anesthesia is neurotoxic in infants and children does not seem farfetched, and has fueled an exponential rise of both basic and clinical investigations and publications.2 The evolving nature of preclinical investigations in anesthetic neurotoxicity has not only identified subtle behavioral impairments in nonhuman primates, but also uncovered new insights into mechanisms of general anesthesia. In his article in this issue of the Journal, Barnes3 declares that it is “time to stop” pediatric anesthesia neurotoxicity research based on clinical findings of studies supporting the lack of neurocognitive deficits associated with general anesthesia. He points to no causation between anesthesia exposure and later neurocognitive difficulties in twin studies, sibling studies, and the only randomized prospective trial to date, the General Anesthesia Compared to Spinal Anesthesia Study (GAS) trial, which compared the outcomes of infants randomized to either general anesthesia or regional anesthesia for inguinal hernia repair.4–6 Taken together, these reports provide compelling evidence that short-to-moderate length anesthesia exposure at a young age does not affect neurocognitive outcomes in terms of overall intelligence and school readiness. However, these rigorous investigations tell us nothing about the long-term effects of prolonged or repeated anesthetic exposures in young children. Recently, a cohort of 212 survivors of childhood acute lymphoblastic leukemia from a single tertiary-care pediatric institution underwent neurocognitive testing and neuroimaging.7 After adjusting for chemotherapeutic doses and age of diagnosis, higher propofol cumulative dose, volatile anesthetic exposure, and longer anesthesia duration were individually associated with neurocognitive impairment. On average, these children underwent almost 16 hours of anesthesia and 27 anesthetic exposures during their treatment. However, as Barnes3 points out, “Children are given anesthetics in order to undergo surgery or other procedures, making it extraordinarily difficult to eliminate the possibility that any findings are indicative of association but not causation.” Because these patients were from a single institution subjected to the same clinical protocols, the children with more frequent anesthetic exposures probably required more procedures due to complications of treatment or severity of initial illness. Both lead to prolonged hospitalizations, social isolation, and concurrent medications and therapies. These are known confounders that directly impact neurocognitive development. An alternative explanation for the neurological impairments in this group of young oncology patients is that stressed and frail patients may be vulnerable to the ostensible toxic effects of anesthesia drugs. This might fit into the stress diathesis model in which patients who have an underlying vulnerability when stressed are likely to develop long-term adverse sequelae, whereas resilient patients given the same stressors will likely not develop adverse sequelae.8 The stressors occurring during anesthetic exposure might include anesthetic neurotoxicity, hypotension, hypocapnia, or hypoxia.9 Other stressors occurring as a result of the surgical procedures include systemic inflammation, which has been shown to affect neurocognition in adults. It is impossible to determine which explanation is correct, or if both explanations are correct, from this retrospective study design. So, essentially, we are left in the same place we were when the first retrospective large cohort studies were published many years ago that showed an association between general anesthesia exposure and later neurocognitive disabilities. Another take-home message from this study was the sheer number of general anesthetics that children are exposed to if they are unlucky enough to develop a serious illness. The factors that lead to poor neurocognitive outcomes in patients with major illnesses, including the effects of frequent and prolonged anesthetic exposures, need to be studied. In this same issue, Ing et al10 reported increased utilization of medications for attention deficit hyperactivity disorder (ADHD) in children who were exposed to general anesthesia at a young age. This finding supports a previous report linking anesthesia and surgery to ADHD. For instance, the data analyzed by Ing et al10 may be deeply confounded by the choice of procedures. Figures 2D and 3E reveal a relatively high hazard ratio for persistent utilization of ADHD medication in patients exposed after 2 years of age and undergoing tonsillectomy and adenoidectomy, respectively. Because the most common indication for tonsillectomy and adenoidectomy in the United States is obstructive sleep apnea, it stands to reason that there would be a high percentage of these patients treated for ADHD as well as other behavioral problems, such as enuresis, because these conditions are associated with obstructive sleep apnea.11 From a public health standpoint, research and funding should also be directed toward examining the factors and confounders that impact pediatric anesthesia care to improve neurocognitive outcomes. Ultimately, clinical answers are what our colleagues demand, not experimental observations in the laboratory. Most of the retrospective studies have relied on databases that are already populated with information about outcome measures such as school readiness tests, referrals for educational help or neurobehavioral medical diagnoses. When compared to randomized controlled trials or prospective comparisons of cohort, retrospective database analyses are less expensive and time consuming to perform. The effort, time, and money to explore these databases are minimal. So the argument that a great deal of research money is funding studies in which the research question is already settled does not hold water. The argument can be and should be made that these type of retrospective database analyses are so confounded that any associations found are specious. Furthermore, retrospective observations do not confirm causation. The fact that parents, families, and caregivers being unduly concerned about the neurotoxic effects of anesthesia is a real issue. In our experience, the best response to this concern is for anesthesiologists to be aware and conversant about the available literature. Generally, parents in our practice have their concerns allayed about both potential neurotoxicity and overall immediate risks of general anesthesia when they are presented with the data. In a perverse way, undue parental concern may be a marker of those parents who need extra information and time to feel comfortable with their child undergoing anesthesia and surgery. It is the responsibility of the anesthesiologists to make sure that proceduralists, be they surgeons, endoscopists, or imaging specialists, are up to date on the real risks of general anesthesia for young children. If the potential of repeated anesthetic or prolonged duration of anesthetic exposure makes some proceduralist pause in their deliberations about whether a certain examination is absolutely necessary, that is probably a good thing. Finally, we would like to make the argument that research on pediatric anesthetic neurotoxicity has broader implications for all those children who require prolonged sedation in intensive care units. The mean length of time for sedation and neuromuscular paralysis for patients undergoing procedures for long gap esophageal atresia repair by traction sutures is reported to be 14 days for primary repairs and 35 days for secondary repairs.12 Although we agree with Barnes3 that the sole concern should not be on developing anesthetic regimens that are less neurotoxic, we do feel that research into developing alternative regimens for sedation for prolonged intensive care may benefit patients by decreasing anesthetic neurotoxicity as well as improving hemodynamic stability. Prolonged sedation may also provoke withdrawal syndrome in these vulnerable patients. The real costs of prolonged sedation for our young patients are just being explored, and the potential for neurotoxicity of these agents is just one of the many concerns regarding these children. Barnes,3 appropriately, is trying to shift the attention away from “potential toxins” to the real concerns about how we need to improve the conduct of pediatric anesthesia. We wholeheartedly agree and, in fact, would like to broaden the mandate of pediatric anesthesiologists to examine all aspects of pediatric care and determine ways that it can be improved. As the specialty that cares for children in the operating room, intensive care units, and pain clinics, we are uniquely positioned to take on the challenge of determining which factors are most important in assuring optimal care for our patients. This approach will have to be collaborative, innovative, and multifactorial. Now that the question has been spoken, it behooves us to diligently develop strategies to keep neurologically intact children normal during serious illness and to limit any further adverse neurological sequelae in children who are already compromised. DISCLOSURES Name: Mary Ellen McCann, MD, MPH. Contribution: This author helped conceive and design the editorial, analyze and interpret the data, draft and revise the manuscript, and approve the final manuscript. Name: Sulpicio G. Soriano, MD. Contribution: This author helped conceive and design the editorial, analyze and interpret the data, draft and revise the manuscript, and approve the final manuscript. This manuscript was handled by: James A. DiNardo, MD, FAAP.

Introduction Randomized trials are important for generating high-quality evidence, but are perceived as difficult to perform in the pediatric population. Thus far there has been poor characterization of the barriers to conducting trials involving children, and the variation in these barriers between countries remains undescribed. The General Anesthesia compared to Spinal anesthesia (GAS) trial, conducted in seven countries between 2007 and 2013, provides an opportunity to explore these issues. Methods We undertook a descriptive analysis to evaluate the reasons for variation in enrollment between countries in the GAS trial, looking specifically at the number of potential subjects screened, and the subsequent application of four exclusion criteria that were applied in a hierarchical order. Results A total of 4023 patients were screened by 28 centers in seven countries. Australia and the USA screened the most subjects, accounting for 84% of all potential trial participants. The percentage of subjects eliminated from the screened pool by each exclusion criterion varied between countries. Exclusion due to a predefined condition (H1) eliminated only 5% of potential subjects in Italy and the UK, but 37% in Canada. Exclusions due to a contraindication or a physician's refusal most impacted enrollment in Australia and the USA. The patient being "too large for spinal anesthesia" was the most commonly cited by anesthetists who refused to enroll a patient (64% of anesthetist refusals). The majority of surgeon refusals came from the USA, where surgeons preferred the patient to receive a general anesthetic. The percentage of approached parents refusing to consent ranged from a low of 3% in Italy to a high of 70% in the USA and Netherlands. The most frequently cited reason for parent refusal in all countries was a preference for general anesthesia (median: 43%, range: 32%-67%). However, a sizeable proportion of parents in all countries had a contrasting preference for spinal anesthesia (median: 25%, range: 13%-31%), and 23% of U.S. parents expressed concern about randomization. Conclusion The GAS trial highlights enrollment challenges that can occur when conducting multicenter, international, pediatric studies. Investigators planning future trials should be aware of potential differences in screening processes across countries, and that exclusions by anesthetists and surgeons may vary in reason, in frequency, and by country. Furthermore, investigators should be aware that the U.S. centers encountered particularly high surgeon and parental refusal rates and that U.S. parents were uniquely concerned about randomization. Planning trials that address these difficulties should increase the likelihood of successfully recruiting subjects in pediatric trials.

Background In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. Methods In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-to-treat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. Findings Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41-70). The mean FSIQ score was 99.08 (SD 18.35) in the awake-regional anaesthesia group and 98.97 (19.66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0.23 (95% CI -2.59 to 3.06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. Interpretation Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Abstract General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.

Infants who undergo surgical procedures in the first few months of life are at a higher risk of death or subsequent neurodevelopmental abnormalities. Although the pathogenesis of these outcomes is multifactorial, an understanding of the nature and pathogenesis of brain injury in these infants may assist the anesthesiologist in consideration of their day-to-day practice to minimize such risks. This review will summarize the main types of brain injury in preterm and term infants and their key pathways. In addition, the review will address key potential pathogenic pathways that may be modifiable including intraoperative hypotension, hypocapnia, hyperoxia or hypoxia, hypoglycemia, and hyperthermia. Each of these conditions may increase the risk of perioperative neurological injury, but their long-term ramifications are unclear.