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.

Postoperative mortality in children after 101,885 anesthetics at a tertiary pediatric hospital.

BACKGROUND: Mortality is a basic measure for quality and safety in anesthesia. There are few anesthesia-related mortality data available for pediatric practice. Our objective for this study was to determine the incidence of 24-hour and 30-day mortality after anesthesia and to determine the incidence and nature of anesthesia-related mortality in pediatric practice at a large tertiary institution. METHODS: Children ≤ 18 years old who had an anesthetic between January 1, 2003, and August 30, 2008, at the Royal Children's Hospital, Melbourne, Australia, were included for this study. Data were analyzed by merging a database for every anesthetic performed with an accurate electronic record of mortality of children who had ever been a Royal Children's Hospital patient. Cases of children dying within 30 days and 24 hours of an anesthetic were identified and the patient history and anesthetic record examined. Anesthesia-related death was defined as those cases whereby a panel of 3 senior anesthesiologists all agreed that anesthesia or factors under the control of the anesthesiologist more likely than not influenced the timing of death. RESULTS: During this 68-month period, 101,885 anesthetics were administered to 56,263 children. The overall 24-hour mortality from any cause after anesthesia was 13.4 per 10,000 anesthetics delivered and 30-day mortality was 34.5 per 10,000 anesthetics delivered. The incidence of death was highest in children ≤ 30 days old. Patients undergoing cardiac surgery had a higher incidence of 24-hour and 30-day mortality than did those undergoing noncardiac surgery. From 101,885 anesthetics there were 10 anesthesia-related deaths. The incidence of anesthesia-related death was 1 in 10,188 or 0.98 cases per 10,000 anesthetics performed (95%confidence interval, 0.5 to 1.8). In all 10 cases, preexisting medical conditions were identified as being a significant factor in the patient's death. Five of these cases (50%) involved children with pulmonary hypertension. CONCLUSIONS: Anesthesia-related mortality is higher in children with heart disease and in particular those with pulmonary hypertension. The lack of anesthetic-related deaths in children who did not have major comorbidities reinforces the safety of pediatric anesthesia in healthy children.

Implicit memory formation during routine anesthesia in children: a double-masked randomized controlled trial.

BACKGROUND: Implicit memory cannot be consciously recalled but may be revealed by changes in behavior. There is evidence for implicit memory formation during anesthesia in adults, but several studies in children have found no evidence for implicit memory. This may be due to insensitive testing. Also many of these tests were undertaken under controlled conditions. It remains unknown whether implicit memory is formed during routine pediatric anesthesia. The aim of this study was to determine whether there is evidence of implicit memory formation during routine anesthesia in children, using a degraded auditory stimulus recognition task. METHODS: Three hundred and twelve children, aged 5-12 yr, were randomly assigned to be played either a sheep sound or white noise continuously through headphones during general anesthesia. No attempt was made to standardize the anesthetic. On recovery, children were played a sheep sound degraded by a white noise mask that progressively decreased over 60 s, with the outcome being the time taken to correctly recognize the sheep sound. RESULTS: Three hundred children completed the task. A comparison of the distribution of recognition times between the two groups found little evidence that exposure to a sheep sound during anesthesia was associated with postoperative time to recognition of a degraded sheep sound (hazard ratio 1.14, 95% CI of 0.90-1.43, P = 0.28). CONCLUSION: No implicit memory formation during routine anesthesia was demonstrated in children. It is increasingly likely that the potential clinical implications of implicit memory formation are less of a concern for pediatric anesthetists.

Detecting awareness in children by using an auditory intervention.

BACKGROUND: The incidence of awareness has been reported to be higher in children than in adults. Accurately assessing awareness in children is difficult, and the lack of a specific measure of awareness makes it difficult to determine exactly how many and why children are aware. The aim of this study was to determine the incidence and timing of awareness in children by using auditory stimuli applied during anesthesia. METHODS: Three easily identified animal noises were played repeatedly through headphones during three specific phases of anesthesia in 539 children aged 5-12 yr. Children were not told that this would happen. Awareness was determined with a structured interview on days 1 and 3 after the anesthetic. All positive responses were sent to four adjudicators for assessment, and awareness was defined as having occurred if all adjudicators agreed that the child was aware. RESULTS: Five hundred children were interviewed at least once after the anesthetic. Thirty-five reports were sent to the adjudicators, and one child was classified as aware. This child was deemed to be aware even though he did not report hearing an animal. CONCLUSIONS: The incidence of awareness in this study is less than reported previously.