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, 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, GAS consortium, Andrew J Davidson, Geoff Frawley, Pollyanna Hardy, Sarah J Arnup, Tibor Schuster, Katherine Lee, Rodney W Hunt, Robyn Stargatt, Suzette Sheppard, Gillian D Ormond, Penelope L Hartmann, Michael J Takagi, Stephanie Malarbi, Melissa Doyle, Philip Ragg, Marie Backstrom, David Costi, Britta S von Ungern-Sternberg, Niall C Wilton, Graham Knottenbelt, Nicola Disma, Giovanni Montobbio, Leila Mameli, Pietro Tuo, Gaia Girbaldi, Alessio Pini Prato, Girolamo Mattioli, Andrea Wolfler, Francesca Izzo, Ida Salvo, Valter Sonzogni, Bruno Guido Locatelli, Magda Khotcholava, Jurgen C de Graaff, Jose T D G van Gool, Sandra C Numan, D Judy S van Veldhuijzen, Cor J Kalkman, Anneloes L van Baar, Leonie J P Steenis, J H M Hagenaars, Anthony R Absalom, Frouckje M Hoekstra, Martin Volkers, Davinia Withington, Koto Furue, Josee Gaudreault, Mary Ellen McCann, Charles Berde, Sulpicio Soriano, Vanessa Young, 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, Jeffery Steiner, Brian Kravitz, Suresh Surantham, Stephen Hays, Andreas Taenzer, Lynne Maxwell, Robert K Williams, Neil S Morton, Graham Bell, Liam Dorris, Claire Adey, Jaycee Pownall, Oliver Bagshaw, Anthony Chisakuta, Ayman Eissa, Peter Stoddart, Annette Davis, Paul Myles, Andrew J Davidson, Mary Ellen McCann, Neil S Morton, Nicola Disma, Davinia E Withngton, Jurgen C deGraaff, Geoff Frawley, Rodney W Hunt, David C Bellinger, Charles Berde, Andy Wolf, Neil McIntosh, John Carlin, Kate Leslie, Jonathan de Lima, Greg Hammer, David Field, Val Gebski, Dick Tibboel, 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, 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, GAS consortium, Andrew J Davidson, Geoff Frawley, Pollyanna Hardy, Sarah J Arnup, Tibor Schuster, Katherine Lee, Rodney W Hunt, Robyn Stargatt, Suzette Sheppard, Gillian D Ormond, Penelope L Hartmann, Michael J Takagi, Stephanie Malarbi, Melissa Doyle, Philip Ragg, Marie Backstrom, David Costi, Britta S von Ungern-Sternberg, Niall C Wilton, Graham Knottenbelt, Nicola Disma, Giovanni Montobbio, Leila Mameli, Pietro Tuo, Gaia Girbaldi, Alessio Pini Prato, Girolamo Mattioli, Andrea Wolfler, Francesca Izzo, Ida Salvo, Valter Sonzogni, Bruno Guido Locatelli, Magda Khotcholava, Jurgen C de Graaff, Jose T D G van Gool, Sandra C Numan, D Judy S van Veldhuijzen, Cor J Kalkman, Anneloes L van Baar, Leonie J P Steenis, J H M Hagenaars, Anthony R Absalom, Frouckje M Hoekstra, Martin Volkers, Davinia Withington, Koto Furue, Josee Gaudreault, Mary Ellen McCann, Charles Berde, Sulpicio Soriano, Vanessa Young, 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, Jeffery Steiner, Brian Kravitz, Suresh Surantham, Stephen Hays, Andreas Taenzer, Lynne Maxwell, Robert K Williams, Neil S Morton, Graham Bell, Liam Dorris, Claire Adey, Jaycee Pownall, Oliver Bagshaw, Anthony Chisakuta, Ayman Eissa, Peter Stoddart, Annette Davis, Paul Myles, Andrew J Davidson, Mary Ellen McCann, Neil S Morton, Nicola Disma, Davinia E Withngton, Jurgen C deGraaff, Geoff Frawley, Rodney W Hunt, David C Bellinger, Charles Berde, Andy Wolf, Neil McIntosh, John Carlin, Kate Leslie, Jonathan de Lima, Greg Hammer, David Field, Val Gebski, Dick Tibboel

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).

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile

References

    1. Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, et al. Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. British journal of anaesthesia. 2013;111(2):143–151.
    1. Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L. Developmental Stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology. 2011;115(2):282–293.
    1. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876–882.
    1. Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, et al. General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain. Anesthesiology. 2011;115(5):992–1002.
    1. Istaphanous GK, Ward CG, Nan X, Hughes EA, McCann JC, McAuliffe JJ, et al. Characterization and quantification of isoflurane-induced developmental apoptotic cell death in mouse cerebral cortex. Anesthesia and analgesia. 2013;116(4):845–854.
    1. Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33(2):220–230.
    1. Raper J, Alvarado MC, Murphy KL, Baxter MG. Multiple Anesthetic Exposure in Infant Monkeys Alters Emotional Reactivity to an Acute Stressor. Anesthesiology. 2015
    1. Slikker W, Jr, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci. 2007;98(1):145–158.
    1. Brambrink AM, Back SA, Riddle A, Gong X, Moravec MD, Dissen GA, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Annals of neurology. 2012;72(4):525–535.
    1. Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112(4):834–841.
    1. Hansen TG. Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children. Paediatric anaesthesia. 2015;25(1):65–72.
    1. Psaty BM, Platt R, Altman RB. Neurotoxicity of generic anesthesia agents in infants and children: an orphan research question in search of a sponsor. Jama. 2015;313(15):1515–1516.
    1. Rappaport BA, Suresh S, Hertz S, Evers AS, Orser BA. Anesthetic neurotoxicity--clinical implications of animal models. The New England journal of medicine. 2015;372(9):796–767.
    1. Crosby G, Davis PJ. General anesthesia in infancy is associated with learning disabilities-or not. Anesthesia and analgesia. 2013;117(6):1270–1272.
    1. Davidson AJ. Anesthesia and neurotoxicity to the developing brain: the clinical relevance. Paediatric anaesthesia. 2011;21(7):716–721.
    1. DiMaggio C, Sun LS, Ing C, Li G. Pediatric anesthesia and neurodevelopmental impairments: a Bayesian meta-analysis. Journal of neurosurgical anesthesiology. 2012;24(4):376–381.
    1. Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476–e485.
    1. Ing CH, DiMaggio CJ, Malacova E, Whitehouse AJ, Hegarty MK, Feng T, et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology. 2014;120(6):1319–1332.
    1. Lei SY, Hache M, Loepke AW. Clinical research into anesthetic neurotoxicity: does anesthesia cause neurological abnormalities in humans? Journal of neurosurgical anesthesiology. 2014;26(4):349–357.
    1. Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5):e1053–e1061.
    1. Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanic K, et al. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clinic proceedings. 2012;87(2):120–129.
    1. Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796–804.
    1. DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesthesia and analgesia. 2011;113(5):1143–1151.
    1. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. Journal of neurosurgical anesthesiology. 2009;21(4):286–291.
    1. Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12(3):246–253.
    1. Hansen TG, Pedersen JK, Henneberg SW, Pedersen DA, Murray JC, Morton NS, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;114(5):1076–1085.
    1. Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Paediatric anaesthesia. 2013;23(10):883–890.
    1. Block RI, Thomas JJ, Bayman EO, Choi JY, Kimble KK, Todd MM. Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology. 2012;117(3):494–503.
    1. Bong CL, Allen JC, Kim JT. The effects of exposure to general anesthesia in infancy on academic performance at age 12. Anesthesia and analgesia. 2013;117(6):1419–1428.
    1. Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta-regression. PloS one. 2014;9(1):e85760.
    1. Davidson AJ, Becke K, de Graaff J, Giribaldi G, Habre W, Hansen T, et al. Anesthesia and the developing brain: a way forward for clinical research. Paediatric anaesthesia. 2015;25(5):447–452.
    1. Davidson AJ, Morton NS, Arnup SJ, de Graaff JC, Disma N, Withington DE, et al. Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, A Randomized Controlled Trial. Anesthesiology. 2015;123(1):38–54.
    1. Frawley G, Bell G, Disma N, Withington DE, de Graaff JC, Morton NS, et al. Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes. Anesthesiology. 2015;123(1):55–65.
    1. Bayley N. Bayley Scales of Infant and Toddler Development. 3rd. San Antonio: Harcourt Assessment Inc; 2006.
    1. Fenson L, Marchman VA, Thal DJ, Dale PS, Reznic JS, Bates E. MacArthur-Bates Communicative Development Inventories: User’s Guide and Technical Manual. 2nd. Baltimore Brookes Publishing; 2007.
    1. van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Statistical methods in medical research. 2007;16(3):219–242.
    1. Seaman SR, White IR. Review of inverse probability weighting for dealing with missing data. Statistical methods in medical research. 2013;22(3):278–295.
    1. Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice. Journal of neurosurgical anesthesiology. 2008;20(1):21–28.
    1. Di Maggio C, Sun L, Kakavuoli A, Byrne M, Li G. A retrspective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. Journal of neurosurgical anesthesiology. 2009;21:286–291.
    1. Harris SR, Langkamp DL. Predictive value of the Bayley mental scale in the early detection of cognitive delays in high-risk infants. Journal of perinatology : official journal of the California Perinatal Association. 1994;14(4):275–279.
    1. Bode MM, D’Eugenio DB, Mettelman BB, Gross SJ. Predictive validity of the Bayley, Third Edition at 2 years for intelligence quotient at 4 years in preterm infants. Journal of developmental and behavioral pediatrics : JDBP. 2014;35(9):570–575.
    1. Lee BH, Chan JT, Kraeva E, Peterson K, Sall JW. Isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females. Neuropharmacology. 2014;83:9–17.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться