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.

Implicit memory formation using the word stem completion task during anesthesia in children.

AIMS: To determine whether there is evidence of implicit memory formation during pediatric anesthesia using the word stem completion task. BACKGROUND: In adults, there is mixed evidence for implicit memory formation during anesthesia; however, there is no evidence in children. Implicit memory in adults has been detected using the word stem completion task. This test has not been used in a pediatric anesthetic setting. METHODS: A total of 200 patients aged 7-12 were randomized to hear one of the two lists of 10 words played continuously while anesthetized. Group 1 heard List A and Group 2 heard List B. Postoperatively, 194 completed a word stem completion task where they were required to complete the stems (the first part of words) corresponding to the words on the two word lists combined, with the first word that came to mind. RESULTS: Group 1 completed a mean of 2.78 words correctly from List A and a mean of 2.70 words correctly from List B. Group 2 completed a mean of 3.29 words correctly from List A and a mean of 3.66 words correctly from List B. For List A, there was no evidence (P = 0.70) for an association between intraoperative exposure to this list and the odds of successfully completing a stem from this list with the corresponding target word. There was little evidence (P = 0.09) for an association with List B. CONCLUSION: This study found no strong evidence that children form implicit memories for auditory words during anesthesia. Given the difference between lists, future research is warranted using carefully chosen word stems.

The severity and duration of postoperative pain and analgesia requirements in children after tonsillectomy, orchidopexy, or inguinal hernia repair.

OBJECTIVES: To provide parents of children with accurate information regarding postoperative pain, its management, and functioning following common surgical procedures. BACKGROUND: The increasing prevalence of pediatric day-case procedures demands a more thorough understanding of the recovery profiles associated with these operations. AIM: To document postdischarge pain profiles, analgesia requirements, and functional limitation in children following tonsillectomy, orchidopexy, or inguinal hernia repair (IHR). METHODS: Following hospital discharge, parents were asked to record their children's pain levels, analgesia consumption, and degree of functional limitation each day until complete recovery. Pain and functional limitation were measured using the Parents' Postoperative Pain Measurement (PPPM) scale and Functional Activity Score, respectively. Significant pain was defined as PPPM ≥ 6. RESULTS: One hundred and five patients (50, tonsillectomy; 24, orchidopexy; and 31, IHR) were recruited. Median PPPM was always <6 after IHR, ≥6 only on day 1 after orchidopexy and persisted through to day 8 after tonsillectomy. Mild or severe functional limitation was observed after all surgeries and persisted for 4, 5, and 4 days after median PPPM < 6 after IHR, orchidopexy, and tonsillectomy, respectively. Combination analgesia was commonly administered after orchidopexy and tonsillectomy but less so after IHR. The general practitioner consultation rate following tonsillectomy was 54%. CONCLUSIONS: After tonsillectomy, children experience significant pain and severe functional limitation for 7 days after surgery. For many children, pain and functional limitation persists throughout the second postoperative week. In children undergoing orchidopexy, paracetamol and ibuprofen provide adequate analgesia. Pain begins to subside after the first postoperative day, and normal activity resumes after 7 days. After IHR, children experience mild pain that can be treated with paracetamol and return to normal functioning after 4 days.

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.

Behavior and quality of life measures after anesthesia for tonsillectomy or ear tube insertion in children.

BACKGROUND: Past research examining the psychosocial impact of general anesthesia and day case surgery on children has been hampered by a lack of valid and reliable assessment tools. AIM: The purpose of the current study was to assess the feasibility of using a well-validated scale (i.e. the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0, PedsQL) in the perioperative setting and to establish changes seen in a sample of children having day case surgery when using this scale. METHOD: Eighty-nine children (aged 3-12 years) scheduled for general anesthesia for day case tonsillectomy or ear tube insertions were recruited into a prospective study in Melbourne, Australia. Parents completed the PedsQL and the Post Hospitalization Behavioral Questionnaire (PHBQ), and children completed the PedsQL (child self-report) at baseline (preanesthesia), 7 days following anesthesia and 30 days following anesthesia. RESULTS: The response rate at day 7 and day 30 was modest but when returned the PedsQL and PHBQ had minimal missing data. On the PedsQL, parents rated children's physical functioning as worse at day 7 than at baseline but psychosocial functioning did not differ significantly from baseline. At 30 days, both physical and psychosocial functioning was rated by parents to be better than baseline levels. From children's perspective, there was little evidence of a change in their physical or psychosocial functioning on the self-report PedsQL at day 7, but by day 30 both physical and psychosocial functioning was above baseline levels. A similar pattern was observed on the PHBQ, with little difference in ratings of behavioral problems between baseline and day 7, but less behavioral problems reported at day 30 compared with baseline. CONCLUSIONS: The PedsQL is feasible for use in the perioperative setting. Future studies should take into account the possibility that deterioration of psychosocial functioning is uncommon at 1 -month postsurgery compared to the preoperative baseline.

Study to assess the laryngeal and pharyngeal spread of topical local anesthetic administered orally during general anesthesia in children.

BACKGROUND: Topical local anesthesia of the airway of anaesthetized children has many potential benefits. In our institution, lignocaine is topically instilled blindly into the back of the mouth with the expectation that it will come into contact with the larynx. The volume and method of application varies between clinicians. There is no published evidence to support the plausibility of this technique. AIM: To determine whether this technique of instillation results in the local anesthetic coming into contact with key laryngeal structures and whether this is influenced by volume or additional physical maneuvers. METHODS/MATERIALS: Sixty-three healthy anaesthetized children between 6 months and 16 years old had lignocaine stained with methylene blue poured into the back of their mouths. The volume and subsequent physical maneuver were determined by randomization. A blinded observer assessed staining of the vocal cords, epiglottis, vallecula and piriform fossae by direct laryngoscopy. Airway complications were recorded. RESULTS: Fifty-three of the 63 children had complete staining of all four areas. Four children had one area unstained, and all others had at least partial staining of all four structures. Nine children coughed following induction of anesthesia. Coughing was more likely in children with incomplete staining (P = 0.03), low volume lignocaine (P = 0.003) and following a head lift (P = 0.02). CONCLUSION: Oral administration of lignocaine without use of a laryngoscope frequently results in widespread coverage of key laryngeal structures and may reduce the risk of coughing.

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.

MAC-awake of sevoflurane in children.

INTRODUCTION: Age influences the potency of anesthetic agents, but there is little information on how age influences MAC-awake. MAC-awake may be an important aspect of anesthesia potency for the prevention of awareness during anesthesia. The aim of this study was to measure MAC-awake in a range of ages in children. METHODS: After institutional ethics approval and informed parental consent 60 children were enrolled; 20 in each of three age groups (2 to <5, 5 to <8 and 8-12 years). Children were excluded if they had opioids, sedative premedication or a procedure likely to cause any residual discomfort. All children had sevoflurane anesthesia. At the end of the procedure the sevoflurane was decreased to the target concentration. Once the target endtidal concentration was achieved it was maintained for 10 min before a standard stimulus was applied and an observer determined if the child was awake. The Dixon up-down method was used to determine progression of subsequent concentrations and MAC-awake (ED50) for the three age groups were obtained using the probit model. RESULTS: This study found evidence for a difference in ED50 between age groups (P = 0.008). The MAC-awake was highest in the youngest group (0.66%) and similar in the older groups (0.45% and 0.43%). CONCLUSION: Although MAC-awake changes with age, in the ages where awareness has been reported, MAC-awake was found to be relatively low, and therefore it seems unlikely that age-specific changes to MAC-awake are a cause for awareness in children aged 5-12 years.

The electroencephalograph during anesthesia and emergence in infants and children.

BACKGROUND: The characteristics of the electroencephalogram (EEG) during anesthesia in children are poorly described. An understanding of the EEG during anesthesia may help explain and predict the performance of EEG-derived depth of anesthesia monitors in children. This study aims to describe the association between age and some basic characteristics of the EEG during nonstandardized anesthesia in children and infants. METHODS: Sixty-four children aged 9 days to 12 years were enrolled in this observational physiological study. Anesthesia was given at the discretion of the anesthetist. EEG was recorded from after induction to emergence using a BRM2 brain monitor ''BrainZ Instruments, Auckland, New Zealand'' in parietal and frontal montages. For comparison, 90% spectral edge frequency (SEF-90) and power were determined at three points (equilibrium during anesthesia, when the volatile agent was discontinued and at emergence), and children were divided into three age groups (0-6 months, 6-24 months and 2-12 years). RESULTS: Fifty-seven children had artifact-free EEG data. From equilibrium to emergence the mean forehead power decreased substantially in children aged 2-12 years (3171-153 microV(2), P < 0.001) and 6-24 months (756-140 microV(2), P < 0.001) but no difference was found in infants aged 0-6 months (93-63 microV(2), P = 0.4). From equilibrium to emergence mean forehead spectral edge frequency increased in children aged 2-12 years (10.8-13.7 Hz, P = 0.01) but no change was found in children aged 6-24 months (12.7-12.7 Hz, P = 0.9) or 0-6 months (9.45-7.26 Hz, P = 0.08). Throughout emergence, infants demonstrated a discontinuous EEG pattern with intermittent bursts separated with low amplitude. CONCLUSIONS: During anesthesia, the EEG in infants is fundamentally different from the EEG in older children. This study supports the need for specific infant-derived algorithms if EEG-derived anesthesia depth monitors are to be used in infants.