Robyn Stargatt

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled 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-totreat 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.Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. 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. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

Neurocognitive Consequences of Risk-Adapted Therapy for Childhood Medulloblastoma

PURPOSE This prospective, longitudinal study examined the effects of risk-adapted craniospinal irradiation (CSI) dose and the interactions of dose with age and time from diagnosis on intelligence quotient (IQ) and academic achievement (reading, spelling, and math) among patients treated for medulloblastoma (MB). PATIENTS AND METHODS Patients received serial neurocognitive testing spanning from 0 to 6.03 years after diagnosis (median, 3.14 years). The multi-institutional study included 111 patients, who were 3 to 20 years of age at diagnosis (median age, 7.4 years), treated for MB with risk-adapted CSI followed by four cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, and vincristine) with stem-cell support. High-risk patients (HR; n = 37) received CSI to 36 to 39.6 Gy and conformal boost treatment of the primary site to 55.8 to 59.4 Gy. Average-risk patients (AR; n = 74) received CSI to 23.4 Gy and conformal boost treatment of the posterior fossa to 36.0 Gy and primary site to 55.8 Gy. RESULTS Multivariate modeling revealed statistically significant declines in mean IQ (-1.59 points/yr; P = .006), reading (-2.95 points/yr; P < .0001), spelling (-2.94 points/yr; P < .0001), and math (-1.87 points/yr; P = .003) scores for the entire group. The effects of risk-adapted radiation therapy on IQ, reading, and spelling were moderated by age, with the greatest rates of decline observed for the HR patients who were younger (< 7 years old) at diagnosis. CONCLUSION Young age at diagnosis was the most prominent risk factor for neurocognitive deficits among survivors of MB despite reductions in CSI dosing and efforts to limit the boost volume. Younger patients exhibited substantial problems with the development of reading skills.

Awareness during anesthesia in children : A prospective cohort study

During routine adult anesthesia, the risk of awareness is 0.1%–0.2%. No recent studies have reported the incidence in children. Altered pharmacology and differing anesthesia techniques suggest that the incidence may differ in children. In this prospective cohort study, we determined the incidence of awareness during anesthesia in children. Eight-hundred-sixty-four children aged 5–12 yr who had undergone general anesthesia at The Royal Children’s Hospital were interviewed on 3 occasions to determine the incidence of awareness. The awareness assessment was nested within a larger study of behavior change after anesthesia. Reports of suspected awareness were sent to four independent adjudicators. If they all agreed, a case was classified as true awareness. Twenty-eight reports were generated. There were 7 cases of true awareness, for an incidence of 0.8% (95% confidence interval, 0.3%–1.7%). Only one aware child received neuromuscular blockers, compared with 12% in the nonaware group. No aware child reported distress, and no substantial difference was detected in behavior disturbance between aware (20%) and nonaware (16%) children. The data provide some evidence that, like adults, children are also at risk of intraoperative awareness. Although the cause remains unclear, anesthesiologists should be alerted to the possibility of awareness in children.

Predictors of Acute Child and Family Outcome following Traumatic Brain Injury in Children

Objective: To examine the relative contributions of injury severity, level of physical and cognitive disability, child behavior and family function to short-term outcome 6 months following traumatic brain injury (TBI) in children. Design: Prospective, longitudinal, between-group design, comparing preinjury and postinjury measures of functional outcome across three levels of injury severity. Subjects: One hundred and twelve children, aged 2–12 years admitted to the Royal Children’s Hospital, Melbourne, with a diagnosis of TBI. The sample was divided into three groups, according to injury severity: mild TBI (n = 31), moderate TBI (n = 52) and severe TBI (n = 29). Children with a history of neurologic, developmental and psychiatric disorder were excluded from participation. Main Outcome Measures: Levels of postinjury functioning in the following domains: physical function, cognitive ability (incorporating intellect, memory and attention), behavioral and family functioning, and level of family burden. Results: A clear dose-response relationship for physical and cognitive outcomes was found, with severe TBI associated with greater impairment of physical, intellectual, memory and attentional function. For psychosocial outcome, results were less clearly linked to injury severity. Preinjury behavioral and family functioning were closely related to postinjury function in these domains, with an interaction identified between family function and child behavior at 6 months postinjury. Family functioning remained unchanged postinjury, although level of burden was high, and predicted by injury severity, functional impairment and postinjury behavioral disturbance. Conclusions: These results suggest ongoing functional problems for the child and significant family burden 6 months following TBI. The nature and severity of physical and cognitive problems are most closely related to injury severity, with family functioning and child behavior better predicted by psychosocial and premorbid factors.

A cohort study of the incidence and risk factors for negative behavior changes in children after general anesthesia.

Background:  Hospitalization and anesthesia can have a substantial psychological impact on children, which may be manifested by negative behavioral change. The primary aims of this study were to estimate the incidence of negative behavior change postanesthesia in a large cohort of children, and to identify the possible risk factors.

Risk factors for anxiety at induction of anesthesia in children: a prospective cohort study

Background : In children anxiety at induction of anesthesia is a common and important aspect of the psychological impact of anesthesia and surgery. Previous studies examining risk factors for increased anxiety have found contradictory results. This may be due to using small, or highly selective population samples, or failure to adjust for confounding variables. Results may also be culturally or institutionally specific. The aim of this study was to identify possible risk factors in a large representative cohort of children.

A prospective analysis of the recovery of attention following pediatric head injury

Little is known about specific attentional sequelae following a closed head injury, their pattern of recovery or their interaction with ongoing development. The present study examined attentional abilities in a group of children who had sustained a mild, moderate, or severe head injury. Results showed that the severe head injury group exhibited greater deficits on a number of attentional measures at acute and 6 months postinjury phases, in comparison to children in the mild and moderate head injury groups. Specifically, deficits were most evident on timed tasks where speed of processing was an integral component. Difficulties persisted to at least 6 months postinjury and so may lead to cumulative deficits over time.

Neonatal brain abnormalities and memory and learning outcomes at 7 years in children born very preterm

Using prospective longitudinal data from 198 very preterm and 70 full term children, this study characterised the memory and learning abilities of very preterm children at 7 years of age in both verbal and visual domains. The relationship between the extent of brain abnormalities on neonatal magnetic resonance imaging (MRI) and memory and learning outcomes at 7 years of age in very preterm children was also investigated. Neonatal MRI scans were qualitatively assessed for global, white-matter, cortical grey-matter, deep grey-matter, and cerebellar abnormalities. Very preterm children performed less well on measures of immediate memory, working memory, long-term memory, and learning compared with term-born controls. Neonatal brain abnormalities, and in particular deep grey-matter abnormality, were associated with poorer memory and learning performance at 7 years in very preterm children. Findings support the importance of cerebral neonatal pathology for predicting later memory and learning function.

Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial

Background:Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia. Methods:Infants aged 60 weeks or younger, postmenstrual age scheduled for inguinal herniorrhaphy, were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born less than 26 weeks gestation. The primary outcome of this analysis was any observed apnea up to 12 h postoperatively. Apnea assessment was unblinded. Results:Three hundred sixty-three patients were assigned to RA and 359 to GA. Overall, the incidence of apnea (0 to 12 h) was similar between arms (3% in RA and 4% in GA arms; odds ratio [OR], 0.63; 95% CI, 0.31 to 1.30, P = 0.2133); however, the incidence of early apnea (0 to 30 min) was lower in the RA arm (1 vs. 3%; OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367). The incidence of late apnea (30 min to 12 h) was 2% in both RA and GA arms (OR, 1.17; 95% CI, 0.41 to 3.33; P = 0.7688). The strongest predictor of apnea was prematurity (OR, 21.87; 95% CI, 4.38 to 109.24), and 96% of infants with apnea were premature. Conclusions:RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Cardiorespiratory monitoring should be used for all ex-premature infants.

Multiple Factors Contribute to Neuropsychological Outcome in Children With Posterior Fossa Tumors

Cognitive deficits are frequently reported in children treated for posterior fossa (PF) tumors. A range of tumor, treatment, medical and treatment complications have been implicated in causing a variety of cognitive deficits. The aim of this study is to identify factors that influence intelligence, attention and information processing in these children. Thirty-five children (aged 4–16) with PF tumors attending the Royal Childrens Hospital Melbourne, Australia, were enrolled into a prospective, repeated measures design. Neuropsychological assessments were conducted at diagnosis and at 12 month intervals for three years. The results find that the PF tumor, hydrocephalus, white matter injury and radiation therapy have various impacts on intelligence, attention and information processing skills, and contribute to the long term outcome in children treated for PF tumor. The neurological structures that subserve the efficient function of attention and information processing are particularly vulnerable to those factors.