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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
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).
Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Melbourne Children's Trials Centre, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Department of Anaesthesia and Pain Management, The Royal Children's Hospital, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. Electronic address: andrew.davidson@rch.org.au.
Andrew J
AJ
Davidson
Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy.
Nicola
N
Disma
Department of Anaesthesia, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands.
Jurgen C
JC
de Graaff
Department of Anesthesia, Montreal Children's Hospital, Montreal, Canada; Department of Anesthesia, McGill University, Montreal, Canada.
Davinia E
DE
Withington
Mental Health and Wellbeing, University of Glasgow, Glasgow, UK.
Liam
L
Dorris
Department of Anaesthesia, Royal Hospital for Children, Glasgow, UK.
Graham
G
Bell
School of Psychological Science, La Trobe University, Victoria, VIC, Australia; Child Neuropsychology, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
Robyn
R
Stargatt
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Environmental Health, Harvard T H Chan School of Public Health, Boston, MA, USA.
David C
DC
Bellinger
Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
Tibor
T
Schuster
Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
Sarah J
SJ
Arnup
National Perinatal Epidemiology Unit, Clinical Trials Unit, University of Oxford, Oxford, UK.
Pollyanna
P
Hardy
Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Neonatal Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Department of Neonatal Medicine, The Royal Children's Hospital, Melbourne, Australia.
Rodney W
RW
Hunt
Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Child Neuropsychology, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
Michael J
MJ
Takagi
Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy.
Gaia
G
Giribaldi
Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
Penelope L
PL
Hartmann
Department of Anesthesiology and Pediatric Intensive Care, Ospedale Pediatrico 'Vittore Buzzi', Milan, Italy.
Ida
I
Salvo
Department of Anaesthesia, Royal Hospital for Children, Glasgow, UK; University of Glasgow, Glasgow, UK.
Neil S
NS
Morton
School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia; Department of Anaesthesia and Pain Management, Princess Margaret Hospital for Children, Perth, WA, Australia.
Britta S
BS
von Ungern Sternberg
Department of Anesthesia, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
Bruno Guido
BG
Locatelli
Department of Paediatric Anaesthesia and Operating Rooms, Starship Children's Hospital, Auckland District Health Board, Auckland, New Zealand.
Niall
N
Wilton
Department of Anesthesiology, University of Washington, Seattle, WA, USA.
Anne
A
Lynn
Department of Anesthesia, University of Minnesota, Minneapolis, MN, USA.
Joss J
JJ
Thomas
Department of Anesthesiology, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
David
D
Polaner
Department of Anaesthesia, Birmingham Children's Hospital, Birmingham, UK.
Oliver
O
Bagshaw
Department of Anesthesiology, Children's Medical Centre Dallas, Dallas, TX, USA.
Peter
P
Szmuk
Department of Anaesthesiology, University Medical Centre Groningen, Groningen University, Groningen, Netherlands.
Anthony R
AR
Absalom
Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Department of Anaesthesia and Pain Management, The Royal Children's Hospital, Melbourne, VIC, Australia.
Geoff
G
Frawley
Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Charles
C
Berde
Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
Gillian D
GD
Ormond
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Jacki
J
Marmor
Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Mary Ellen
ME
McCann
D000367:Age Factors; D000768:Anesthesia, General / Q000009:adverse effects* / Q000379:methods; D000775:Anesthesia, Spinal / Q000009:adverse effects* / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D002657:Child Development / Q000187:drug effects*; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D005865:Gestational Age; D006552:Hernia, Inguinal / Q000601:surgery; D059685:Herniorrhaphy / Q000009:adverse effects; D006801:Humans; D007223:Infant; D008297:Male; D014888:Wechsler Scales