Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial

Mary Ellen Mccann, Jurgen C De Graaff, Liam Dorris, Nicola Disma, Davinia Withington, Graham Bell, Anneke Grobler, Robyn Stargatt, Rodney W Hunt, Suzette J Sheppard, Jacki Marmor, Gaia Giribaldi, David Bellinger, Penelope L Hartmann, Pollyanna Hardy, Geoff Frawley, Francesca Izzo, Britta Von Ungern-sternberg, Anne Lynn, Niall WiltonMartin Mueller, David M Polaner, Anthony R Absalom, Peter Szmuk, Neil S Morton, Charles Berde, Sulpicio Soriano, Andrew J Davidson, Andrew J Davidson, Geoff Frawley, Pollyanna Hardy, Sarah Arnup, Anneke Grobler, Katherine Lee, Rod W Hunt, Robyn Stargatt, Suzette J Sheppard, Gillian D Ormond, Penelope L Hartmann, Michael J Takagi, Kaitlyn Taylor, Stephanie Malarbi, Melissa Doyle, Philip Ragg, David Costi, Britta Von Ungern-sternberg, Niall C Wilton, Graham Knottenbelt, Davinia Withington, Koto Furue, Hélène Gagnon, Nicola Disma, Leila Mameli, Gaia Giribaldi, Alessio Pini Prato, Girolamo Mattioli, Andrea Wolfler, Francesca Izzo, Stefania M Bova, Arianna Krachmalnicoff, Claudia Guuva, Jurgen C De Graaff, Desiree Bm Van Der Werff, Jose Tdg Van Gool, Kim Van Loon, Cor J Kalkman, Anneloes L Van Baar, Anthony R Absalom, Frouckje M Hoekstra, Martin Volkers, Martine Oostra, Graham Bell, Liam Dorris, Neil S Morton, Jaycee Pownall, Jack Waldman, Ruth Hind, Joseph D Symonds, Oliver Bagshaw, Mary Ellen Mccann, Charles Berde, Sulpicio Soriano, Navil Sethna, Pete Kovatsis, Joseph Cravero, David Bellinger, Jacki Marmor, Anne Lynn, Iskra Ivanova, Agnes Hunyady, Shilpa Verma, David Polaner, Joss Thomas, Martin Mueller, Denisa Haret, Peter Szmuk, Jeffrey Steiner, Brian Kravitz, Alan Farrow-gillespie, Santhanam Suresh, Stephen Hays, Andreas Taenzer, Lynne Maxwell, Robert Williams

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)664-677
JournalThe Lancet
Volume393
Issue number10172
DOIs
Publication statusPublished - 1 Feb 2019

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