Elsevier

The Lancet

Volume 387, Issue 10015, 16–22 January 2016, Pages 239-250
The Lancet

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

https://doi.org/10.1016/S0140-6736(15)00608-XGet rights and content

Summary

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).

Introduction

Substantial preclinical evidence exists that describes how general anaesthesia drugs change brain development in young animals.1 These changes include accelerated apoptosis and other effects such as changes to dendritic morphology.2, 3, 4, 5 Findings have also shown that exposure to general anaesthesia in young animals is associated with long-term cognitive and behavioural changes.3, 6, 7 These effects have been described in various species including non-human primates.7, 8, 9, 10 The changes are seen with several different general anaesthesia drugs, are greater with longer exposure, and are less severe in older animals.2, 8 The clinical relevance of these findings is unknown and much debated.11, 12, 13, 14

In human beings, there is conflicting evidence for an association between exposure to anaesthesia in early childhood and adverse long-term neurodevelopmental outcome; however, confounding restricts any assumption of causality.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 Young children who receive anaesthesia are inevitably having surgery or an investigative procedure. Added risk of poor neurodevelopmental outcome might be due to the underlying pathology, comorbidity, or other perioperative risk factors. These results have prompted recommendations to consider delaying surgery in infancy and there have been several calls for more research to address this important issue.12, 13, 31

Research in context

Evidence before this study

We searched MEDLINE and Cochrane controlled trial register (last search done on Sept 18, 2015) for original research and meta-analyses describing the association between anaesthesia exposure in early life and neurodevelopmental outcome. We used combinations of the search terms “anesthesia”, and “child development”, or “learning disorders”. The search found no randomised trials but several cohort studies. Several reviews have concluded that there is an association between anaesthesia in childhood and neurodevelopmental outcome. Findings of two meta-analyses have shown an association between anaesthesia in children and a range of neurodevelopmental outcomes. All reviews and meta-analyses acknowledge the weaknesses of the cohort studies; including strong likelihood of confounding, bias, heterogeneous populations at times of exposure, and heterogeneous outcome measures, some of which are poorly defined or insensitive. All reviews conclude that causation cannot be established or excluded.

Added value of this study

We report results from the first randomised controlled trial assessing the effect of general anaesthesia in infancy on neurodevelopmental outcome. We used the best measure of neurodevelopment available to assess 2-year-old children, and noted strong evidence for equivalence between the use of awake-regional anaesthesia and just less than 1 h of general anaesthesia. However, it should be noted that this was an analysis of a secondary outcome with the primary outcome planned at 5 years of age, and in view of the limited sensitivity of developmental assessment at 2 years of age, this trial does not provide the definitive answer.

Implications of all the available evidence

Although there are some limitations that should be noted when interpreting the trial, the randomised prospective design adds substantially to the weight that should be given to the results compared with the mixed results found in previous cohort studies. However, reassessment at an older age is necessary before definitive conclusions can be drawn. The trial does not rule out the possibility that longer or many exposures to anaesthesia in early childhood can cause neurodevelopmental changes. Further research is needed to address these questions.

In view of the many potential confounding factors, a randomised trial is the best study design to establish whether anaesthesia exposure in early childhood causes long-term neurodevelopmental changes. Fortuitously there are two established anaesthetic techniques for inguinal herniorrhaphy in infancy; awake-regional and sevoflurane-based general anaesthesia. Therefore, we undertook a randomised controlled trial comparing neurodevelopmental outcome in children who were randomly assigned to receive either awake-regional or sevoflurane-based general anaesthesia for inguinal herniorrhaphy in early infancy: the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. The primary outcome for 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. As a secondary outcome, we also planned a priori to assess neurodevelopmental outcome at age 2 years. In this paper we report all secondary outcomes at 2 years of age. Data from the trial relating to post-anaesthesia apnoea and success of regional block have been published elsewhere.32, 33

Section snippets

Study design

In this observer-blind, international, multisite, randomised, controlled, equivalence trial, we assessed awake-regional anaesthesia versus general anaesthesia in infants undergoing inguinal herniorrhaphy. The trial was done at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Institutional review board or ethics committee approval was obtained at each site and written consent obtained from the child's parents or guardians. A summary of the protocol is

Results

Between Feb 9, 2007, and Jan 31, 2013, we recruited 722 infants from 28 hospitals in Australia, the USA, the UK, Italy, the Netherlands, Canada, and New Zealand (appendix p4). There were two misrandomisations and one withdrawal of consent leaving 361 in the intention-to-treat analysis in the awake-regional anaesthesia group and 358 in the general anaesthesia group (figure). Table 1 summarises demographic data for each group at baseline and table 2 summarises demographic data at 2 years. There

Discussion

We noted strong evidence for equivalence between awake-regional anaesthesia and general anaesthesia in infancy in terms of neurodevelopmental outcome at 2 years of age. Equivalence was shown in many domains of neurodevelopmental assessment and the 95% CIs fell within a third of an SD, well inside our predefined boundaries of clinical equivalence.

There are no previous randomised trials assessing the effect of anaesthesia in infancy on long-term neurodevelopmental outcomes. Previous cohort

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