A framework for individualized splice-switching oligonucleotide therapy.

Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.

Rescue designs in analgesic trials from 0 to 2 years of age: scoping review.

Pediatric analgesic trials are challenging, especially in newborns and infants. Following an FDA-academic consensus meeting, we analyzed pragmatic rescue designs in postoperative trials of local anesthetics, acetaminophen, opioids, and NSAIDs involving children ages 0-2 years and assessed surgical volumes to provide trial design recommendations. Searches of PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science were conducted. A scoping approach identified trends in analgesic trials with an emphasis on randomized controlled trials (RCTs) utilizing immediate rescue designs. Age-specific surgical volumes were estimated from French national databases. Of 3563 studies identified, 23 RCTs used study medication(s) of interest and immediate rescue paradigms in children ages 0-2 years. A total of 270 studies met at least one of these criteria. Add-on and head-to-head designs were common and often used sparing of non-opioid or opioid rescue medication as a primary outcome measure. According to French national data, inguinal and penile surgeries were most frequent in ages 1 month to 2 years; abdominal and thoracic surgeries comprise approximately 75% of newborn surgeries. Analgesic trials with rescue sparing paradigm are currently sparse among children ages 0-2 years. Future trials could consider age-specific surgical procedures and use of add-on or head-to-head designs. IMPACT: Clinical trials of analgesic medications have been challenging in pediatrics, especially in the group from newborns to 2 years of age. Following an FDA-academic workshop, we analyzed features of completed analgesic trials in this age group. Studies using immediate rescue in placebo control, add-on, and head-to-head trial designs are pragmatic approaches that can provide important information regarding clinical effectiveness, side effects, and safety. Using a French national dataset with a granular profile of inpatient, outpatient, and short-stay surgeries, we provide information to future investigators on relative frequencies of different operations in neonates and through the first 2 years of life.

Emerging functional connectivity patterns during sevoflurane anaesthesia in the developing human brain.

BACKGROUND: Spectral-based EEG is used to monitor anaesthetic state during surgical procedures in adults. Spectral EEG features that can resemble the patterns seen in adults emerge in children after the age of 10 months and cannot distinguish wakefulness and anaesthesia in the youngest children. There is a need to explore alternative EEG measures. We hypothesise that functional connectivity is one of the measures that can help distinguish between consciousness states in children. METHODS: An EEG data set of children undergoing sevoflurane general anaesthesia (age 0-3 yr) was reanalysed using debiased weighted phase lag index as a measure of functional connectivity in wakefulness (n=38) and anaesthesia (n=73). Network topology measures were compared between states in 0- to 6-, 6- to 10-, and >10-month-old children. RESULTS: Functional connectivity was reduced in anaesthesia vs wakefulness in delta band (n=cluster of 17 significant connections; P=0.013; 58% connections surviving thresholding in wakefulness and 49% in anaesthesia). Network density and node degree were lower in anaesthesia even in the youngest children (0.57 in wakefulness; 0.48 in anaesthesia; t [9]=3.39; P=0.029; G=0.98; confidence interval [CI] [0.25-1.77]). Modularity was higher in anaesthesia (0-6 months: 0.16 in wakefulness and 0.19 in anaesthesia, t [9]=-2.95, P=0.04, G=-0.85, CI [-1.60 to -0.16]; >10 months: 0.16 vs 0.21, t [13]=-6.45, P<0.001, G=-1.62, CI [-2.49 to -0.85]) and decreased with age (ρ [73]=-0.456; P<0.001). CONCLUSIONS: Anaesthesia modulates functional connectivity. Increased segregation into a more modular structure in anaesthesia decreases with age as adult-like features develop. These findings advance our understanding of the network architecture underlying the effects of anaesthesia on the developing brain.

Electroencephalographic delta and alpha oscillations reveal phase-amplitude coupling in paediatric patients undergoing sevoflurane-based general anaesthesia.

BACKGROUND: Sevoflurane-induced anaesthesia generates frontal alpha oscillations as early as 6 months of age, whereas strong delta oscillations are present at birth. In adults, delta oscillations and alpha oscillations are coupled: the phase of delta waves modulates the amplitude of alpha oscillations in a phenomenon known as phase-amplitude coupling. We hypothesise that delta-alpha phase-amplitude coupling exists in young children and is a feature of sevoflurane-based general anaesthesia distinct from emergence after anaesthesia. METHODS: Electroencephalographic data from 31 paediatric patients aged 10 months to 3 yr undergoing elective surgery with sevoflurane-based anaesthesia were analysed retrospectively. Delta-alpha phase-amplitude coupling was evaluated during maintenance of anaesthesia and during emergence. RESULTS: Delta-alpha phase-amplitude coupling was observed in the study population. Strength of phase-amplitude coupling, represented by the delta-alpha mean amplitude vector, was greater during general anaesthesia than during emergence (Wilcoxon paired signed-rank test, Z=3.107, P=0.002). Frontal alpha amplitude during anaesthesia was not uniformly distributed across all delta phases. During general anaesthesia, alpha power was restricted to the positive phase of the delta wave (omnibus circular uniformity, general anaesthesia: P<0.001, mean phase: 114º; 99% confidence interval: 90º-139º; emergence: P=0.35, mean phase 181º, 99% confidence interval: 110º-253º). CONCLUSIONS: Sevoflurane-based anaesthesia is associated with delta-alpha phase-amplitude coupling in paediatric patients. These findings improve our understanding of cortical dynamics in children undergoing general anaesthesia, which might improve paediatric intraoperative depth of anaesthesia monitoring techniques.

Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).

Epidural catheter placement in children with baclofen pumps.

BACKGROUND: Children with cerebral palsy often suffer from increased tone, which can be treated with intrathecal baclofen via implanted pump. Additionally, they often require major orthopedic surgery for hip reconstruction; however, the presence of an intrathecal baclofen pump is a relative contraindication to regional anesthesia due to concerns about damaging the intrathecal baclofen pump system. AIMS: (a) To evaluate adverse events related to placing epidural catheters in children with intrathecal baclofen pumps and (b) describe our multidisciplinary approach to the care of these complex patients. METHODS: Children with cerebral palsy and intrathecal baclofen pump in situ who underwent hip reconstruction between 2010 and 2019 and had a perioperative epidural placed were reviewed retrospectively. Charts were assessed for adverse events or intrathecal baclofen complications. Fluoroscopic images were reviewed to evaluate the proximity between epidural and intrathecal baclofen catheters. The process of coordinating multiple services was examined. RESULTS: Sixteen children met the inclusion criteria. There were no major complications following epidural placement. Postoperative pump interrogation was normal for all patients. Fluoroscopy was utilized for 9/16 (56%) epidural procedures. Epidurogram was used to confirm 11/16 catheters (68%). Children with an intrathecal baclofen pump were identified by orthopedic surgeons at the time of surgical booking and referred to the regional anesthesia team for review. The neurosurgical, pain, and regional anesthesia teams determined the appropriateness and safety of approaching the neuraxis. Pain and/or regional anesthesiologists with competency in spine fluoroscopy were scheduled on the day of surgery for fluoroscopically guided epidural placement. Postoperatively, catheters were managed by the acute pain team. Intrathecal baclofen pumps were interrogated by the baclofen pump team prior to patient discharge. DISCUSSION: In this case series, not only was epidural placement feasible but also there were no observed complications. This work highlights the importance of a multidisciplinary approach to complex regional anesthetic techniques, as well as the importance of basic competency in spine fluoroscopy for regional anesthesiologists.

Intrathecal catheter and port placement for nusinersen infusion in children with spinal muscular atrophy and spinal fusion.

BACKGROUND: Spinal administration of medications is challenging in patients with complete posterior spinal fusion. We describe percutaneous image-guided intrathecal port placement for administration of the antisense oligonucleotide nusinersen for children and young adults with spinal muscular atrophy. OBJECTIVE: To describe and present our initial experience with a new technique for administering nusinersen in patients with spinal muscular atrophy and posterior spinal fusion. MATERIALS AND METHODS: We reviewed medical records of 13 patients who received intrathecal ports using DynaCT, biplane fluoroscopy and iGuide from April 2018 through June 2019, and we describe the clinical course over 1 year. RESULTS: Image-guided catheter and port implantation was successful in all cases. Two ports were subsequently removed, one for persistent cerebrospinal fluid leak and one for superficial infection. The other 11 have functioned successfully for a minimum of 23 months. CONCLUSION: We report our experience with image-guided intrathecal port placement in children with complete posterior spine fusion. The implanted port permits dosing in an outpatient setting and avoids the need for multiple future radiologic procedures, and it reduces discomfort, procedural costs and potential risks and sequelae of multiple anesthetics and radiation exposures. Further studies are needed to define the relative risks and benefits of intrathecal ports compared to other approaches such as repeated transforaminal lumbar punctures.

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial.

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. FUNDING: US National Institutes of Health, US Food and Drug Administration, Thrasher Research Fund, Australian National Health and Medical Research Council, Health Technologies Assessment-National Institute for Health Research (UK), Australian and New Zealand College of Anaesthetists, Murdoch Children's Research Institute, Canadian Institutes of Health Research, Canadian Anesthesiologists Society, Pfizer Canada, Italian Ministry of Health, Fonds NutsOhra, UK Clinical Research Network, Perth Children's Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.

Off-label use of prescription analgesics among hospitalized children in the United States.

PURPOSE: Analgesics are the most frequently administered medications among hospitalized children. However, current analgesic prescribing patterns have not been well defined among hospitalized children. In addition, it is unknown what proportion of prescription analgesics is approved for use in children and what proportion is used "off-label." METHODS: Nationally representative data from 52 tertiary care children's hospitals in the Pediatric Health Information System were queried to determine prescribing rates of analgesic medications. We analyzed hospitalizations for children <18 years occurring between 1 April 2010 and 30 June 2018. Food and Drug Administration (FDA) drug labels were reviewed for pediatric information, and prescriptions were classified as on- or off-label based on age, route, and formulation. RESULTS: Among 4.9 million hospitalizations, 1.8 million (37.6%, 95% confidence interval [CI] = 37.6-37.7) were associated with use of a prescription analgesic. Overall, 36.7% (95% CI = 36.7-36.7) of hospitalizations included off-label analgesic therapy, with 26.4% (95% CI = 26.4-26.5) associated with two or more off-label analgesics. Off-label analgesic use was higher among hospitalizations in the intensive care unit (61.5%) or with an operating room procedure (92.8%). Rates of off-label prescribing increased with age, peaking at 50.5% for adolescents. Prescription analgesics administered most frequently were morphine, fentanyl, and ketorolac, with off-label use occurring in 24.5%, 23.1%, and 11.3% of hospitalizations, respectively. CONCLUSIONS: Over a third of pediatric hospitalizations were associated with the administration of prescription analgesics that have not been labeled for use in children. Our findings highlight the critical need to ensure that safe and effective analgesics are developed for children and that pediatric labeling is expanded for existing analgesics to inform treatment decisions.

Case Studies Using the Electroencephalogram to Monitor Anesthesia-Induced Brain States in Children.

For this child, at this particular moment, how much anesthesia should I give? Determining the drug requirements of a specific patient is a fundamental problem in medicine. Our current approach uses population-based pharmacological models to establish dosing. However, individual patients, and children in particular, may respond to drugs differently. In anesthesiology, we have the advantage that we can monitor our patients in real time and titrate drugs to the desired effect. Examples include blood pressure management or muscle relaxation. Although the brain is the primary site of action for sedative-hypnotic drugs, the brain is not routinely monitored during general anesthesia or sedation, a fact that would surprise many patients. One reason for this is that, until recently, physiologically principled approaches for anesthetic brain monitoring have not been articulated. In the past few years, our knowledge of anesthetic brain mechanisms has developed rapidly. We now know that anesthetic drug effects are clearly visible in the electroencephalogram (EEG) of adults and reflect underlying anesthetic pharmacology and brain mechanisms. Most recently, similar effects have been characterized in children. In this article, we describe how EEG monitoring could be used to guide anesthetic management in pediatric patients. We review previous evidence and present multiple case studies showing how drug-specific and dose-dependent EEG signatures seen in adults are visible in children and infants, including those with neurological disorders. We propose that the EEG can be used in the anesthetic care of children to enable anesthesiologists to better assess the drug requirements of individual patients in real time and improve patient safety and experience.

δ-Oscillation Correlates of Anesthesia-induced Unconsciousness in Large-scale Brain Networks of Human Infants.

BACKGROUND: Functional brain connectivity studies can provide important information about changes in brain-state dynamics during general anesthesia. In adults, γ-aminobutyric acid-mediated agents disrupt integration of information from local to the whole-brain scale. Beginning around 3 to 4 months postnatal age, γ-aminobutyric acid-mediated anesthetics such as sevoflurane generate α-electroencephalography oscillations. In previous studies of sevoflurane-anesthetized infants 0 to 3.9 months of age, α-oscillations were absent, and power spectra did not distinguish between anesthetized and emergence from anesthesia conditions. Few studies detailing functional connectivity during general anesthesia in infants exist. This study's aim was to identify changes in functional connectivity of the infant brain during anesthesia. METHODS: A retrospective cohort study was performed using multichannel electroencephalograph recordings of 20 infants aged 0 to 3.9 months old who underwent sevoflurane anesthesia for elective surgery. Whole-brain functional connectivity was evaluated during maintenance of a surgical state of anesthesia and during emergence from anesthesia. Functional connectivity was represented as networks, and network efficiency indices (including complexity and modularity) were computed at the sensor and source levels. RESULTS: Sevoflurane decreased functional connectivity at the δ-frequency (1 to 4 Hz) in infants 0 to 3.9 months old when comparing anesthesia with emergence. At the sensor level, complexity decreased during anesthesia, showing less whole-brain integration with prominent alterations in the connectivity of frontal and parietal sensors (median difference, 0.0293; 95% CI, -0.0016 to 0.0397). At the source level, similar results were observed (median difference, 0.0201; 95% CI, -0.0025 to 0.0482) with prominent alterations in the connectivity between default-mode and frontoparietal regions. Anesthesia resulted in fragmented modules as modularity increased at the sensor (median difference, 0.0562; 95% CI, 0.0048 to 0.1298) and source (median difference, 0.0548; 95% CI, -0.0040 to 0.1074) levels. CONCLUSIONS: Sevoflurane is associated with decreased capacity for efficient information transfer in the infant brain. Such findings strengthen the hypothesis that conscious processing relies on an efficient system of integrated information transfer across the whole brain.

The effect of suprainguinal fascia iliaca block on the recovery of patients after arthroscopic hip surgery.

BACKGROUND: Adolescent and young adult patients undergoing arthroscopic hip surgery experience significant pain in the immediate postoperative period. There is a small body of evidence that indicates suprainguinal fascia iliaca blocks can improve comfort during recovery from this intervention. Our hypothesis was that patients undergoing hip surgery would consume fewer opioids and have less pain in the perioperative time frame if they received the block as part of their analgesic regimen. METHODS: In this study, we evaluated the outcomes of 716 patients, including 275 who received a suprainguinal fascia iliaca block, and 441 who did not have a block. Inclusion criteria included all age groups and American Society of Anesthesiologists, functional classes 1-2. Patients who received other concurrent procedures or those with incomplete data sets were excluded. We utilized a regional anesthesia database that combined data from various repositories into one web-based relational system. The primary outcomes were total opioid consumption and pain scores in the recovery room. Secondary outcomes included opioid side effects, block-related complications, and total recovery room time. Multivariable logistic regression analysis was used to evaluate opioid consumption, side effects, and total recovery times. Pearson chi-square was applied to assess the level of pain between the two groups. RESULTS: Total opioid consumption was significantly less in the block group compared to those not receiving a block (0.28 mg/kg vs 0.35 mg/kg, P < 0.001, 95% CI of difference in medians 0.04-0.10 mg/kg), but there was no statistical difference in pain scores. Patients with the regional block had a lower frequency of emesis in the PACU (0.7% vs 4.3%; P < 0.005, 95% CI of difference: 2-25) and shorter PACU times (93 vs 108 minutes, P < 0.001, 95% CI of difference: 8-23 minutes). CONCLUSION: Our study supports the clinical effectiveness of suprainguinal fascia iliaca blocks in young patients undergoing arthroscopic hip surgery.

The Society for Pediatric Anesthesia recommendations for the use of opioids in children during the perioperative period.

Opioids have long held a prominent role in the management of perioperative pain in adults and children. Published reports concerning the appropriate, and inappropriate, use of these medications in pediatric patients have appeared in various publications over the last 50 years. For this document, the Society for Pediatric Anesthesia appointed a taskforce to evaluate the available literature and formulate recommendations with respect to the most salient aspects of perioperative opioid administration in children. The recommendations are graded based on the strength of the available evidence, with consensus of the experts applied for those issues where evidence is not available. The goal of the recommendations was to address the most important issues concerning opioid administration to children after surgery, including appropriate assessment of pain, monitoring of patients on opioid therapy, opioid dosing considerations, side effects of opioid treatment, strategies for opioid delivery, and assessment of analgesic efficacy. Regular updates are planned with a re-release of guidelines every 2 years.

An open label pilot study of a dexmedetomidine-remifentanil-caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study.

BACKGROUND: Concern over potential neurotoxicity of anesthetics has led to growing interest in prospective clinical trials using potentially less toxic anesthetic regimens, especially for prolonged anesthesia in infants. Preclinical studies suggest that dexmedetomidine may have a reduced neurotoxic profile compared to other conventional anesthetic regimens; however, coadministration with either anesthetic drugs (eg, remifentanil) and/or regional blockade is required to achieve adequate anesthesia for surgery. The feasibility of this pharmacological approach is unknown. The aim of this study was to determine the feasibility of a remifentanil/dexmedetomidine/neuraxial block technique in infants scheduled for surgery lasting longer than 2 hours. METHODS: Sixty infants (age 1-12 months) were enrolled at seven centers over 18 months. A caudal local anesthetic block was placed after induction of anesthesia with sevoflurane. Next, an infusion of dexmedetomidine and remifentanil commenced, and the sevoflurane was discontinued. Three different protocols with escalating doses of dexmedetomidine and remifentanil were used. RESULTS: One infant was excluded due to a protocol violation and consent was withdrawn prior to anesthesia in another. The caudal block was unsuccessful in two infants. Of the 56 infants who completed the protocol, 45 (80%) had at least one episode of hypertension (mean arterial pressure >80 mm Hg) and/or movement that required adjusting the anesthesia regimen. In the majority of these cases, the remifentanil and/or dexmedetomidine doses were increased although six infants required rescue 0.3% sevoflurane and one required a propofol bolus. Ten infants had at least one episode of mild hypotension (mean arterial pressure 40-50 mm Hg) and four had at least one episode of moderate hypotension (mean arterial pressure <40 mm Hg). CONCLUSION: A dexmedetomidine/remifentanil neuraxial anesthetic regimen was effective in 87.5% of infants. These findings can be used as a foundation for designing larger trials that assess alternative anesthetic regimens for anesthetic neurotoxicity in infants.

Clinical signs and electroencephalographic patterns of emergence from sevoflurane anaesthesia in children: An observational study.

BACKGROUND: Few studies have systematically described relationships between clinical-behavioural signs, electroencephalographic (EEG) patterns and age during emergence from anaesthesia in young children. OBJECTIVE: To identify the relationships between end-tidal sevoflurane (ETsevoflurane) concentration, age and frontal EEG spectral properties in predicting recovery of clinical-behavioural signs during emergence from sevoflurane in children 0 to 3 years of age, with and without exposure to nitrous oxide. The hypothesis was that clinical signs occur sequentially during emergence, and that for infants aged more than 3 months, changes in alpha EEG power are correlated with clinical-behavioural signs. DESIGN: An observational study. SETTING: A tertiary paediatric teaching hospital from December 2012 to August 2016. PATIENTS: Ninety-five children aged 0 to 3 years who required surgery below the neck. OUTCOME MEASURES: Time-course of, and ETsevoflurane concentrations at first gross body movement, first cough, first grimace, dysconjugate eye gaze, frontal (F7/F8) alpha EEG power (8 to 12 Hz), frontal beta EEG power (13 to 30 Hz), surgery-end. RESULTS: Clinical signs of emergence followed an orderly sequence of events across all ages. Clinical signs occurred over a narrow ETsevoflurane, independent of age [movement: 0.4% (95% confidence interval (CI), 0.3 to 0.4), cough 0.3% (95% CI, 0.3 to 0.4), grimace 0.2% (95% CI, 0 to 0.3); P > 0.5 for age vs. ETsevoflurane]. Dysconjugate eye gaze was observed between ETsevoflurane 1 to 0%. In children more than 3 months old, frontal alpha EEG oscillations were present at ETsevoflurane 2.0% and disappeared at 0.5%. Movement occurred within 5 min of alpha oscillation disappearance in 99% of patients. Nitrous oxide had no effect on the time course or ETsevoflurane at which children showed body movement, grimace or cough. CONCLUSION: Several clinical signs occur sequentially during emergence, and are independent of exposure to nitrous oxide. Eye position is poorly correlated with other clinical signs or ETsevoflurane. EEG spectral characteristics may aid prediction of clinical-behavioural signs in children more than 3 months.

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).

Electroencephalographic discontinuity during sevoflurane anesthesia in infants and children.

BACKGROUND: Deep anesthesia in adults may be associated with electroencephalographic (EEG) suppression and higher rates of postoperative complications. Little is known about the impact of anesthetic depth on short- or long-term outcomes in pediatrics. Brain activity monitoring may complement clinical signs of anesthetic depth. This prospective observational study aimed to assess the frequency and degree of profound EEG suppression using multichannel EEG in children during sevoflurane general anesthesia. METHODS: Children aged 0-40 months who required general anesthesia for elective surgery were included. Continuous EEG recordings were performed starting from when anesthesia began and until recovery. Discontinuity was defined as EEG amplitude <25 uV, lasting ≥2 s, and observed in all electrodes across the scalp. Frequency, duration, and inter-event interval of discontinuity events were measured. Relationships between discontinuity events and postnatal age, endtidal sevoflurane concentration (etSEVO), and multiple clinical parameters were analyzed. RESULTS: Discontinuity events were observed in 35/68 children, with a median duration of 10 s (95%CI: 8-12) and a median of 4 events per patient (95%CI: 2-7). Children who had discontinuity events were younger (5.5 months, 95%CI: 3.6-6.5) compared to children who did not have discontinuity events (10.2 months, 95%CI: 6.1-14); (difference between medians, 4.7 months, 95%CI: 2.3-8, P = 0.0002). Younger infants exhibited a higher number of discontinuity events, and the incidence decreased with postnatal age (r68 = -0.53, P < 0.0001). The majority of discontinuity events were observed during the first 30 min of anesthesia (66.4% total events), where etSEVO was >3%. Few discontinuity events were observed during maintenance and none during emergence. Blood pressure, heart rate, tissue oxygen saturation, and endtidal CO2 partial pressure did not change during these events. CONCLUSIONS: Electroencephalographic monitoring may complement clinical signs in providing information about brain homeostasis during general anesthesia. The impact of discontinuity events on immediate and long-term outcomes merits further study.