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 Wilton & 11 others Anne 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

Research output: Contribution to journalArticle

359 Citations (Scopus)

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 (US)
Pages (from-to)239-250
Number of pages12
JournalThe Lancet
Volume387
Issue number10015
DOIs
StatePublished - Jan 16 2016

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Conduction Anesthesia
General Anesthesia
Randomized Controlled Trials
Anesthesia
National Institutes of Health (U.S.)
Intelligence
New Zealand
Gestational Age
Canada
Parturition
Biomedical Technology Assessment
General Anesthetics
Groin
Spinal Anesthesia
Herniorrhaphy
Health
United States Food and Drug Administration
Random Allocation
Child Development
Research

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Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS) : An international multicentre, randomised controlled trial. / Davidson, Andrew J.; Disma, Nicola; De Graaff, Jurgen C.; Withington, Davinia E.; Dorris, Liam; Bell, Graham; Stargatt, Robyn; Bellinger, David C.; Schuster, Tibor; Arnup, Sarah J.; Hardy, Pollyanna; Hunt, Rodney W.; Takagi, Michael J.; Giribaldi, Gaia; Hartmann, Penelope L.; Salvo, Ida; Morton, Neil S.; Von Ungern Sternberg, Britta S.; Locatelli, Bruno Guido; Wilton, Niall; Lynn, Anne; Thomas, Joss J.; Polaner, David; Bagshaw, Oliver; Szmuk, Peter; Absalom, Anthony R.; Frawley, Geoff; Berde, Charles; Ormond, Gillian D.; Marmor, Jacki; McCann, Mary Ellen.

In: The Lancet, Vol. 387, No. 10015, 16.01.2016, p. 239-250.

Research output: Contribution to journalArticle

Davidson, AJ, Disma, N, De Graaff, JC, Withington, DE, Dorris, L, Bell, G, Stargatt, R, Bellinger, DC, Schuster, T, Arnup, SJ, Hardy, P, Hunt, RW, Takagi, MJ, Giribaldi, G, Hartmann, PL, Salvo, I, Morton, NS, Von Ungern Sternberg, BS, Locatelli, BG, Wilton, N, Lynn, A, Thomas, JJ, Polaner, D, Bagshaw, O, Szmuk, P, Absalom, AR, Frawley, G, Berde, C, Ormond, GD, Marmor, J & McCann, ME 2016, 'Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): An international multicentre, randomised controlled trial', The Lancet, vol. 387, no. 10015, pp. 239-250. https://doi.org/10.1016/S0140-6736(15)00608-X
Davidson, Andrew J. ; Disma, Nicola ; De Graaff, Jurgen C. ; Withington, Davinia E. ; Dorris, Liam ; Bell, Graham ; Stargatt, Robyn ; Bellinger, David C. ; Schuster, Tibor ; Arnup, Sarah J. ; Hardy, Pollyanna ; Hunt, Rodney W. ; Takagi, Michael J. ; Giribaldi, Gaia ; Hartmann, Penelope L. ; Salvo, Ida ; Morton, Neil S. ; Von Ungern Sternberg, Britta S. ; Locatelli, Bruno Guido ; Wilton, Niall ; Lynn, Anne ; Thomas, Joss J. ; Polaner, David ; Bagshaw, Oliver ; Szmuk, Peter ; Absalom, Anthony R. ; Frawley, Geoff ; Berde, Charles ; Ormond, Gillian D. ; Marmor, Jacki ; McCann, Mary Ellen. / Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS) : An international multicentre, randomised controlled trial. In: The Lancet. 2016 ; Vol. 387, No. 10015. pp. 239-250.
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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).",
author = "Davidson, {Andrew J.} and Nicola Disma and {De Graaff}, {Jurgen C.} and Withington, {Davinia E.} and Liam Dorris and Graham Bell and Robyn Stargatt and Bellinger, {David C.} and Tibor Schuster and Arnup, {Sarah J.} and Pollyanna Hardy and Hunt, {Rodney W.} and Takagi, {Michael J.} and Gaia Giribaldi and Hartmann, {Penelope L.} and Ida Salvo and Morton, {Neil S.} and {Von Ungern Sternberg}, {Britta S.} and Locatelli, {Bruno Guido} and Niall Wilton and Anne Lynn and Thomas, {Joss J.} and David Polaner and Oliver Bagshaw and Peter Szmuk and Absalom, {Anthony R.} and Geoff Frawley and Charles Berde and Ormond, {Gillian D.} and Jacki Marmor and McCann, {Mary Ellen}",
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TY - JOUR

T1 - Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS)

T2 - An international multicentre, randomised controlled trial

AU - Davidson, Andrew J.

AU - Disma, Nicola

AU - De Graaff, Jurgen C.

AU - Withington, Davinia E.

AU - Dorris, Liam

AU - Bell, Graham

AU - Stargatt, Robyn

AU - Bellinger, David C.

AU - Schuster, Tibor

AU - Arnup, Sarah J.

AU - Hardy, Pollyanna

AU - Hunt, Rodney W.

AU - Takagi, Michael J.

AU - Giribaldi, Gaia

AU - Hartmann, Penelope L.

AU - Salvo, Ida

AU - Morton, Neil S.

AU - Von Ungern Sternberg, Britta S.

AU - Locatelli, Bruno Guido

AU - Wilton, Niall

AU - Lynn, Anne

AU - Thomas, Joss J.

AU - Polaner, David

AU - Bagshaw, Oliver

AU - Szmuk, Peter

AU - Absalom, Anthony R.

AU - Frawley, Geoff

AU - Berde, Charles

AU - Ormond, Gillian D.

AU - Marmor, Jacki

AU - McCann, Mary Ellen

PY - 2016/1/16

Y1 - 2016/1/16

N2 - 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).

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).

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