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

Andrew J. Davidson*, Nicola Disma, Jurgen C. De Graaff, Davinia E. Withington, Liam Dorris, Graham Bell, Robyn Stargatt, David C. Bellinger, Tibor Schuster, Sarah J. Arnup, Pollyanna Hardy, Rodney W. Hunt, Michael J. Takagi, Gaia Giribaldi, Penelope L. Hartmann, Ida Salvo, Neil S. Morton, Britta S. Von Ungern Sternberg, Bruno Guido Locatelli, Niall WiltonAnne Lynn, Joss J. Thomas, David Polaner, Oliver Bagshaw, Peter Szmuk, Anthony R. Absalom, Geoff Frawley, Charles Berde, Gillian D. Ormond, Jacki Marmor, Mary Ellen McCann

*Corresponding author for this work

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Abstract

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).

Original languageEnglish
Pages (from-to)239-250
Number of pages12
JournalThe Lancet
Volume387
Issue number10015
DOIs
Publication statusPublished - 16 Jan 2016
Externally publishedYes

Bibliographical note

Funding Information:
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, Pfi zer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN). All hospitals and centres were generously supported by departmental funding. In addition to this funding, specific grants received for this study are as follows: Australia: The Australian National Health & Medical Research Council (Project Grants #1002906 and 491226); Australian and New Zealand College of Anaesthetists (Project Grant #11/021 and 07/012); Murdoch Childrens Research Institute; Victorian Government''s Operational Infrastructure Support Program. US: National Institute of Health (Project Grant # NIH 1-R01 hD06 1136-01A1); Food and Drug Administration (Project Grant #FDA-SOL-08-SAFEKIDS-Clin 002-Project 2). Italy: Italian Ministry of Heath, Young Researchers Grant (Project Grant #167/GR-2009-1476067). Netherlands: Fonds NutsOhra grant #1305-144 and Vrienden WKZ 16.13.038. Canada: Canadian Institute of Health Research (Project Grant #MCT-98031), Canadian Anesthesiologists'' Society, Pfizer Canada Inc. UK: Health Technologies Assessment-National Institute for Health Research UK (Project Grant # 07/01/05). We are also grateful to the following individuals who contributed to the running of the study: Mark Fagjman (Department of Anaesthesia, Monash Medical Centre, Melbourne, VIC, Australia); Daniela Tronconi (Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy); David C van der Zee (Department of Pediatric Surgery, Wilhelmina Children''s Hospital, University Medical Centre Utrecht, Netherlands); Jan Hulscher (Department of Surgery, University Medical Center Groningen, Groningen University, Groningen, Netherlands); Michael Rivkin (Department of Neurology, Children''s Hospital Boston, Boston, MA, USA); Michelle Sadler-Greever (University of Washington, Seattle Children''s Hospital, Department of Anesthesia and Pain Medicine, Seattle, WA, USA); Debra Faulk (Children''s Hospital Colorado and University of Colorado School of Medicine, Department of Anesthesiology, Colorado, CO, USA); Greta Wilkening (Neurosciences Institute, Children''s Hospital Colorado, CO, USA); Edward Goldson (Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Children''s Hospital Colorado, Colorado, USA). Danai Udomtecha and Sarah Titler (The University of Iowa Hospital, Department of Anesthesia, Iowa, IA, USA); Roxana Ploski and Alan Farrow-Gilespie (Children''s Medical Centre Dallas, Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas and Children''s Medical Center at Dallas and Outcome Research Consortium, Dallas, TX, USA); Timothy Cooper (Division of Developmental Medicine and the Center for Child Development, Monroe Carell Jr Children''s Hospital at Vanderbilt, Nashville, TN, USA); Elizabeth Card (Perioperative Clinical Research Institute, Vanderbilt University Medical Center, Nashville, TN, USA); Wendy Boardman (Dartmouth-Hitchcock Medical Center, Department of Anesthesiology, NH, USA); Theodora K Goebel (Department of Anesthesiology and Critical Care Children''s Hospital of Philadelphia, Philadelphia, PA, USA).

Funding Information:
All hospitals and centres were generously supported by departmental funding. In addition to this funding, specific grants received for this study are as follows: Australia: The Australian National Health & Medical Research Council (Project Grants #1002906 and 491226); Australian and New Zealand College of Anaesthetists (Project Grant #11/021 and 07/012); Murdoch Childrens Research Institute; Victorian Government's Operational Infrastructure Support Program. US: National Institute of Health (Project Grant # NIH 1-R01 hD06 1136-01A1); Food and Drug Administration (Project Grant #FDA-SOL-08-SAFEKIDS-Clin 002-Project 2). Italy: Italian Ministry of Heath, Young Researchers Grant (Project Grant #167/GR-2009-1476067). Netherlands: Fonds NutsOhra grant #1305-144 and Vrienden WKZ 16.13.038. Canada: Canadian Institute of Health Research (Project Grant #MCT-98031), Canadian Anesthesiologists' Society, Pfizer Canada Inc. UK: Health Technologies Assessment–National Institute for Health Research UK (Project Grant # 07/01/05). We are also grateful to the following individuals who contributed to the running of the study: Mark Fagjman (Department of Anaesthesia, Monash Medical Centre, Melbourne, VIC, Australia); Daniela Tronconi (Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy); David C van der Zee (Department of Pediatric Surgery, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Netherlands); Jan Hulscher (Department of Surgery, University Medical Center Groningen, Groningen University, Groningen, Netherlands); Michael Rivkin (Department of Neurology, Children's Hospital Boston, Boston, MA, USA); Michelle Sadler-Greever (University of Washington, Seattle Children's Hospital, Department of Anesthesia and Pain Medicine, Seattle, WA, USA); Debra Faulk (Children's Hospital Colorado and University of Colorado School of Medicine, Department of Anesthesiology, Colorado, CO, USA); Greta Wilkening (Neurosciences Institute, Children's Hospital Colorado, CO, USA); Edward Goldson (Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Children's Hospital Colorado, Colorado, USA). Danai Udomtecha and Sarah Titler (The University of Iowa Hospital, Department of Anesthesia, Iowa, IA, USA); Roxana Ploski and Alan Farrow-Gilespie (Children's Medical Centre Dallas, Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas and Children's Medical Center at Dallas and Outcome Research Consortium, Dallas, TX, USA); Timothy Cooper (Division of Developmental Medicine and the Center for Child Development, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA); Elizabeth Card (Perioperative Clinical Research Institute, Vanderbilt University Medical Center, Nashville, TN, USA); Wendy Boardman (Dartmouth-Hitchcock Medical Center, Department of Anesthesiology, NH, USA); Theodora K Goebel (Department of Anesthesiology and Critical Care Children's Hospital of Philadelphia, Philadelphia, PA, USA).

Publisher Copyright:
© 2016 Elsevier Ltd.

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