PMID- 26507180 OWN - NLM STAT- MEDLINE DCOM- 20160401 LR - 20220408 IS - 1474-547X (Electronic) IS - 0140-6736 (Print) IS - 0140-6736 (Linking) VI - 387 IP - 10015 DP - 2016 Jan 16 TI - Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. PG - 239-50 LID - S0140-6736(15)00608-X [pii] LID - 10.1016/S0140-6736(15)00608-X [doi] AB - 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). CI - Copyright (c) 2016 Elsevier Ltd. All rights reserved. FAU - Davidson, Andrew J AU - Davidson AJ AD - 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. FAU - Disma, Nicola AU - Disma N AD - Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy. FAU - de Graaff, Jurgen C AU - de Graaff JC AD - Department of Anaesthesia, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands. FAU - Withington, Davinia E AU - Withington DE AD - Department of Anesthesia, Montreal Children's Hospital, Montreal, Canada; Department of Anesthesia, McGill University, Montreal, Canada. FAU - Dorris, Liam AU - Dorris L AD - Mental Health and Wellbeing, University of Glasgow, Glasgow, UK. FAU - Bell, Graham AU - Bell G AD - Department of Anaesthesia, Royal Hospital for Children, Glasgow, UK. FAU - Stargatt, Robyn AU - Stargatt R AD - School of Psychological Science, La Trobe University, Victoria, VIC, Australia; Child Neuropsychology, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Bellinger, David C AU - Bellinger DC AD - 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. FAU - Schuster, Tibor AU - Schuster T AD - Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Arnup, Sarah J AU - Arnup SJ AD - Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Hardy, Pollyanna AU - Hardy P AD - National Perinatal Epidemiology Unit, Clinical Trials Unit, University of Oxford, Oxford, UK. FAU - Hunt, Rodney W AU - Hunt RW AD - 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. FAU - Takagi, Michael J AU - Takagi MJ AD - Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Child Neuropsychology, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Giribaldi, Gaia AU - Giribaldi G AD - Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy. FAU - Hartmann, Penelope L AU - Hartmann PL AD - Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Salvo, Ida AU - Salvo I AD - Department of Anesthesiology and Pediatric Intensive Care, Ospedale Pediatrico 'Vittore Buzzi', Milan, Italy. FAU - Morton, Neil S AU - Morton NS AD - Department of Anaesthesia, Royal Hospital for Children, Glasgow, UK; University of Glasgow, Glasgow, UK. FAU - von Ungern Sternberg, Britta S AU - von Ungern Sternberg BS AD - 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. FAU - Locatelli, Bruno Guido AU - Locatelli BG AD - Department of Anesthesia, Ospedale Papa Giovanni XXIII, Bergamo, Italy. FAU - Wilton, Niall AU - Wilton N AD - Department of Paediatric Anaesthesia and Operating Rooms, Starship Children's Hospital, Auckland District Health Board, Auckland, New Zealand. FAU - Lynn, Anne AU - Lynn A AD - Department of Anesthesiology, University of Washington, Seattle, WA, USA. FAU - Thomas, Joss J AU - Thomas JJ AD - Department of Anesthesia, University of Minnesota, Minneapolis, MN, USA. FAU - Polaner, David AU - Polaner D AD - Department of Anesthesiology, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA. FAU - Bagshaw, Oliver AU - Bagshaw O AD - Department of Anaesthesia, Birmingham Children's Hospital, Birmingham, UK. FAU - Szmuk, Peter AU - Szmuk P AD - Department of Anesthesiology, Children's Medical Centre Dallas, Dallas, TX, USA. FAU - Absalom, Anthony R AU - Absalom AR AD - Department of Anaesthesiology, University Medical Centre Groningen, Groningen University, Groningen, Netherlands. FAU - Frawley, Geoff AU - Frawley G AD - 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. FAU - Berde, Charles AU - Berde C AD - Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Ormond, Gillian D AU - Ormond GD AD - Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Marmor, Jacki AU - Marmor J AD - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - McCann, Mary Ellen AU - McCann ME AD - Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. CN - GAS consortium LA - eng SI - ANZCTR/ACTRN12606000441516 SI - ClinicalTrials.gov/NCT00756600 GR - FDA-SOL-08-SAFEKIDS-CLIN 002-PROJECT/PHS HHS/United States GR - 1-R01 HD06 1136-01A1/HD/NICHD NIH HHS/United States GR - R01 HD084566/HD/NICHD NIH HHS/United States GR - U54 HD090255/HD/NICHD NIH HHS/United States GR - 07/01/05/DH_/Department of Health/United Kingdom GR - R01 HD061336/HD/NICHD NIH HHS/United States GR - MCT-98031/CAPMC/CIHR/Canada PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20151104 PL - England TA - Lancet JT - Lancet (London, England) JID - 2985213R SB - IM CIN - Lancet. 2016 Jan 16;387(10015):202-4. PMID: 26507181 EIN - Lancet. 2016 Jan 16;387(10015):228. PMID: 26842298 CIN - Lancet. 2016 Apr 16;387(10028):1613. PMID: 27116065 CIN - Lancet. 2016 Apr 16;387(10028):1613-4. PMID: 27116066 CIN - Lancet. 2016 Apr 16;387(10028):1614. PMID: 27116067 CIN - Lancet. 2016 Apr 16;387(10028):1615. PMID: 27116068 CIN - Ann Transl Med. 2016 Oct;4(20):408. PMID: 27867960 MH - Age Factors MH - Anesthesia, General/*adverse effects/methods MH - Anesthesia, Spinal/*adverse effects/methods MH - Brain/drug effects/*growth & development MH - Child Development/*drug effects MH - Child, Preschool MH - Double-Blind Method MH - Female MH - Gestational Age MH - Hernia, Inguinal/surgery MH - Herniorrhaphy/adverse effects MH - Humans MH - Infant MH - Male MH - Wechsler Scales PMC - PMC5023520 MID - NIHMS790283 FIR - Davidson, Andrew J IR - Davidson AJ FIR - Frawley, Geoff IR - Frawley G FIR - Hardy, Pollyanna IR - Hardy P FIR - Arnup, Sarah J IR - Arnup SJ FIR - Schuster, Tibor IR - Schuster T FIR - Lee, Katherine IR - Lee K FIR - Hunt, Rodney W IR - Hunt RW FIR - Stargatt, Robyn IR - Stargatt R FIR - Sheppard, Suzette IR - Sheppard S FIR - Ormond, Gillian D IR - Ormond GD FIR - Hartmann, Penelope L IR - Hartmann PL FIR - Takagi, Michael J IR - Takagi MJ FIR - Malarbi, Stephanie IR - Malarbi S FIR - Doyle, Melissa IR - Doyle M FIR - Ragg, Philip IR - Ragg P FIR - Backstrom, Marie IR - Backstrom M FIR - Costi, David IR - Costi D FIR - von Ungern-Sternberg, Britta S IR - von Ungern-Sternberg BS FIR - Wilton, Niall C IR - Wilton NC FIR - Knottenbelt, Graham IR - Knottenbelt G FIR - Disma, Nicola IR - Disma N FIR - Montobbio, Giovanni IR - Montobbio G FIR - Mameli, Leila IR - Mameli L FIR - Tuo, Pietro IR - Tuo P FIR - Girbaldi, Gaia IR - Girbaldi G FIR - Pini Prato, Alessio IR - Pini Prato A FIR - Mattioli, Girolamo IR - Mattioli G FIR - Wolfler, Andrea IR - Wolfler A FIR - Izzo, Francesca IR - Izzo F FIR - Salvo, Ida IR - Salvo I FIR - Sonzogni, Valter IR - Sonzogni V FIR - Locatelli, Bruno Guido IR - Locatelli BG FIR - Khotcholava, Magda IR - Khotcholava M FIR - de Graaff, Jurgen C IR - de Graaff JC FIR - van Gool, Jose T D G IR - van Gool JT FIR - Numan, Sandra C IR - Numan SC FIR - van Veldhuijzen, D Judy S IR - van Veldhuijzen D FIR - Kalkman, Cor J IR - Kalkman CJ FIR - van Baar, Anneloes L IR - van Baar AL FIR - Steenis, Leonie J P IR - Steenis LJ FIR - Hagenaars, J H M IR - Hagenaars JH FIR - Absalom, Anthony R IR - Absalom AR FIR - Hoekstra, Frouckje M IR - Hoekstra FM FIR - Volkers, Martin IR - Volkers M FIR - Withington, Davinia IR - Withington D FIR - Furue, Koto IR - Furue K FIR - Gaudreault, Josee IR - Gaudreault J FIR - McCann, Mary Ellen IR - McCann ME FIR - Berde, Charles IR - Berde C FIR - Soriano, Sulpicio IR - Soriano S FIR - Young, Vanessa IR - Young V FIR - Sethna, Navil IR - Sethna N FIR - Kovatsis, Pete IR - Kovatsis P FIR - Cravero, Joseph IR - Cravero J FIR - Bellinger, David IR - Bellinger D FIR - Marmor, Jacki IR - Marmor J FIR - Lynn, Anne IR - Lynn A FIR - Ivanova, Iskra IR - Ivanova I FIR - Hunyady, Agnes IR - Hunyady A FIR - Verma, Shilpa IR - Verma S FIR - Polaner, David IR - Polaner D FIR - Thomas, Joss IR - Thomas J FIR - Mueller, Martin IR - Mueller M FIR - Haret, Denisa IR - Haret D FIR - Szmuk, Peter IR - Szmuk P FIR - Steiner, Jeffery IR - Steiner J FIR - Kravitz, Brian IR - Kravitz B FIR - Surantham, Suresh IR - Surantham S FIR - Hays, Stephen IR - Hays S FIR - Taenzer, Andreas IR - Taenzer A FIR - Maxwell, Lynne IR - Maxwell L FIR - Williams, Robert K IR - Williams RK FIR - Morton, Neil S IR - Morton NS FIR - Bell, Graham IR - Bell G FIR - Dorris, Liam IR - Dorris L FIR - Adey, Claire IR - Adey C FIR - Pownall, Jaycee IR - Pownall J FIR - Bagshaw, Oliver IR - Bagshaw O FIR - Chisakuta, Anthony IR - Chisakuta A FIR - Eissa, Ayman IR - Eissa A FIR - Stoddart, Peter IR - Stoddart P FIR - Davis, Annette IR - Davis A FIR - Myles, Paul IR - Myles P FIR - Davidson, Andrew J IR - Davidson AJ FIR - McCann, Mary Ellen IR - McCann ME FIR - Morton, Neil S IR - Morton NS FIR - Disma, Nicola IR - Disma N FIR - Withngton, Davinia E IR - Withngton DE FIR - deGraaff, Jurgen C IR - deGraaff JC FIR - Frawley, Geoff IR - Frawley G FIR - Hunt, Rodney W IR - Hunt RW FIR - Bellinger, David C IR - Bellinger DC FIR - Berde, Charles IR - Berde C FIR - Wolf, Andy IR - Wolf A FIR - McIntosh, Neil IR - McIntosh N FIR - Carlin, John IR - Carlin J FIR - Leslie, Kate IR - Leslie K FIR - de Lima, Jonathan IR - de Lima J FIR - Hammer, Greg IR - Hammer G FIR - Field, David IR - Field D FIR - Gebski, Val IR - Gebski V FIR - Tibboel, Dick IR - Tibboel D EDAT- 2015/10/29 06:00 MHDA- 2016/04/02 06:00 PMCR- 2017/01/16 CRDT- 2015/10/29 06:00 PHST- 2015/10/29 06:00 [entrez] PHST- 2015/10/29 06:00 [pubmed] PHST- 2016/04/02 06:00 [medline] PHST- 2017/01/16 00:00 [pmc-release] AID - S0140-6736(15)00608-X [pii] AID - 10.1016/S0140-6736(15)00608-X [doi] PST - ppublish SO - Lancet. 2016 Jan 16;387(10015):239-50. doi: 10.1016/S0140-6736(15)00608-X. Epub 2015 Nov 4.