A Multi-site Randomized Controlled Trial Comparing Regional and General Anesthesia for Effects on Neurodevelopmental Outcome and Apnea in Infants (GAS)

A Multi-site Randomised Controlled Trial Comparing Regional and General Anaesthesia for Effects on Neurodevelopmental Outcome and Apnoea in Infants

The primary purpose of the GAS study is to determine whether different types of anesthesia (Regional versus General) given to 720 infants undergoing inguinal hernia repair results in equivalent neurodevelopmental outcomes. The study also aims to describe the incidence of apnea in the post-operative period after both regional and general anesthesia for inguinal hernia repair in infants. This study is important as it will provide the greatest evidence for safety or toxicity of general anesthesia for human infants.

Study Overview

• Status: Completed
• Conditions: Inguinal Hernia
• Intervention / Treatment: Drug: Regional Anesthesia; Drug: General Anesthesia

Detailed Description

This is a prospective, observer blind, multi-site, randomized, controlled, equivalence trial. The general anesthesia group will receive sevoflurane (intervention drug) for induction and maintenance of general anesthesia, dose up to 8% inspired for duration of procedure plus bupivacaine local anesthetic blockade (up to 2.5 mg per kg) administered via caudal or ilioinguinal nerve block. The airway can be maintained with a face mask, laryngeal mask or endotracheal tube, with or without neuromuscular blocking agents.

The regional group will have no sedative agent. The regional blockade may be with spinal alone, spinal block with caudal block, spinal with ilioinguinal block or caudal alone. The maximum dose of 2.5 mg per kg of bupivacaine can be used.

• Study Type: Interventional
• Enrollment (Actual): 643
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Adelaide Women's and Children's Hospital
  • Victoria
    • Berwick, Victoria, Australia, 3806
      • Casey Hospital
    • Clayton, Victoria, Australia, 3165
      • Monash Medical Centre
    • Malvern, Victoria, Australia, 3144
      • Cabrini Hospital
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Princess Margaret Hospital
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital
    • Montréal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
• Italy
  • Bergamo, Italy, 24100
    • Ospedali Riuniti di Bergamo
  • Genoa, Italy, 16147
    • G. Gaslini Children's Hospital
  • Milano, Italy, 20100
    • 'Vitore Buzzi' Children's Hospital
• Netherlands
  • Groningen, Netherlands, 9700 RB
    • Universitair Medisch Centrum Groningen
  • Utrecht, Netherlands
    • Wilhelmina Children's Hospital; University Medical Centre Utrecht
• New Zealand
  • Auckland, New Zealand
    • Starship Children's Health
• United Kingdom
  • Belfast, United Kingdom, BT12 6BE
    • Royal Belfast Hospital for Sick Children
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
  • Bristol, United Kingdom, BS2 8BJ
    • Bristol Royal Hospital for Children
  • Glasgow, United Kingdom, G3 8SJ
    • Royal Hospital for Sick Children
  • Liverpool, United Kingdom, L12 2APS
    • Royal Liverpool Children's Hospital
  • Sheffield, United Kingdom, S10 2TS
    • Sheffield Children's Hospital
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital Denver
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • The University of Iowa Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt Children's Hospital
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center of Dallas
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Vermont Children's Hospital at Fletcher Allen Health Care
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Any infant scheduled for unilateral or bilateral inguinal hernia repair (with or without circumcision)
• Any infant whose gestational age is 26 weeks or more (GA = 182 days)
• Any infant whose post-menstrual age is up to 60 weeks (PMA = 426 days)

Exclusion Criteria:

• Any child older than 60 weeks post-menstrual age
• Any child born less than 26 weeks gestation
• Any contraindication to general or spinal/caudal anesthesia (for example: neuromuscular disorder or coagulopathy)
• Pre-operative ventilation immediately prior to surgery
• Congenital heart disease that has required ongoing pharmacotherapy
• Known chromosomal abnormality or any other known acquired or congenital abnormalities (apart from prematurity) which are likely to affect development
• Children where follow-up would be difficult for geographic or social reasons
• Families where English is not the primary language spoken at home
• Known neurological injury such as cystic periventricular leukomalacia (PVL), or grade 3 or 4 intra ventricular hemorrhage (ICH) (+/- post hemorrhage ventricular dilation)
• Previous exposure to volatile anesthesia or benzodiazepines as a neonate or in the third trimester in utero.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Regional Anesthesia	Drug: Regional Anesthesia; Up to 2.5 mg/kg bupivacaine administered by caudal or subarachnoid routes or both caudal and subarachnoid or subarachnoid and ilioinguinal nerve blockade. Single shot.; Other Names: Spinal Anesthesia.
Active Comparator: 2; General Anesthesia	Drug: General Anesthesia; Sevoflurane for induction and maintenance of general anesthesia, dose up to 8% inspired for duration of procedure plus bupivacaine local anesthetic blockade (up to 2.5 mg/kg) administered via caudal or ilioinguinal nerve block.; Other Names: General Anesthesia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Full Scale IQ Score	The primary outcome will be the Wechsler Preschool and Primary Scale of Intelligence-Third Edition (WPPSI-III) full scale IQ score. Verbal, visuo-spatial and processing speed skills are incorporated into the Full Scale IQ score, which is indicative of general intellectual ability. Minimum score: 45 Maximum score:145 Higher scores are associated with higher IQ scores (better outcome). Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years chronological age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Verbal IQ	Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III): Verbal IQ Minimum possible score:45 Maximum possible score:145 A higher score indicates higher verbal IQ (better outcome). Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years corrected age.
Performance IQ	Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III): Performance IQ Minimum possible score:45 Maximum possible score:145 A higher score indicates a higher performance IQ (better outcome). Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years corrected age
Processing Speed Quotient	Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III): Processing speed quotient Minimum possible score:45 Maximum possible score:145 A higher score indicates a better outcome. Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years corrected age
Sentence Repetition Scaled Score	Developmental Neuropsychological Assessment second edition (NEPSY-II) sub test: Sentence Repetition scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years chronological age
Auditory Attention Combined Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Auditory Attention combined scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Statue Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Statue scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Inhibition Combined Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Inhibition combined scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Word Generation Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Word Generation Scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Affect Recognition Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Affect Recognition scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Memory for Names and Memory for Names Delay	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Memory for Names and Memory for Names Delay Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Theory of Mind Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Theory of Mind scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Speeded Naming Combined Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Speeded Naming combined scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Fingertip Tapping Repetitions Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test:Fingertip tapping repetitions scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score is indicative of a better outcome.	At 5 years corrected age
Fingertip Tapping Sequences Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: fingertip tapping sequences scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Design Copy Process Total Scaled Score	Developmental Neuropsychological Assessment Second Edition (NEPSY-II) Sub Test: Design Copy Process Total Scaled Score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years corrected age
Word Reading Standard Score	Weschler Individual Achievement Test (WIAT-II Abbreviated) to assess the academic skills of the child: Word Reading standard score Minimum possible score: 45 Maximum possible score: 145 Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment. A higher score indicates a better outcome.	At 5 years chronological age
Numerical Operations Standard Score	Weschler Individual Achievement Test (WIAT-II Abbreviated) to Assess the Academic Skills of the Child: Numerical Operations standard score Minimum possible score: 45 Maximum possible score: 145 Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment. A higher score indicates a better outcome.	At 5 years chronological age
Spelling Standard Score	Weschler Individual Achievement Test (WIAT-II Abbreviated) to Assess the Academic Skills of the Child: Spelling standard score Minimum possible score: 45 Maximum possible score: 145 A higher score indicates a better outcome. Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years chronological age
Numbers Total Scaled Score	Children's Memory Scale (CMS):Numbers Total scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years chronological age
Word Lists 1 (Learning) Scaled Score	Children's Memory Scale (CMS): Word Lists 1 (learning) scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years chronological age
Memory and Learning Word Lists II (Delayed) Scaled Score	Children's Memory Scale (CMS): Memory and learning Word Lists II (delayed) scaled score Minimum possible score: 1 Maximum possible score: 19 A higher score indicates a better outcome.	At 5 years chronological age
The Global Executive Composite (GEC) of the Behaviour Rating of Executive Function	Full title: The Global Executive Composite (GEC) of the Behaviour Rating of Executive Function Preschool Version Parent Form (BRIEF-P) to measure behavioural executive abilities. Minimum possible score: 40 Maximum possible score: 110 Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment. A higher score indicates a worse outcome.	At 5 years chronological age
The Global Adaptive Composite (GAC) of the Adaptive Behavior Assessment System	Full title: The Global Adaptive Composite (GAC) of the Adaptive Behavior Assessment System - 2nd edition (ABAS-II) to measure the child's adaptive behavior. Minimum possible score: 45 Maximum possible score: 145 A higher score indicates a better outcome. Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years chronological age
Total Problems Score	Child Behaviour Checklist Caregiver Questionnaire (CBCL): Total Problems Score to measure behavioural problems Minimum possible score: 40 Maximum possible score: 100 A higher score indicates a worse outcome. Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years chronological age
Internalising Problems T Score	Child Behaviour Checklist Caregiver Questionnaire (CBCL): CBCL internalising problems T score Minimum possible score: 40 Maximum possible score: 100 A higher score indicates a worse outcome. Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years chronological age
Externalising Problems T Score	Child Behaviour Checklist Caregiver Questionnaire (CBCL): externalising problems T score Minimum possible score: 40 Maximum possible score: 100 A higher score indicates a worse outcome. Note: Scale ranges represent estimates that are very likely to be accurate but which will be verified after access to the physical assessment booklets is restored. The current health situation prohibits the research team from verifying this information at the moment.	At 5 years chronological age
Speech or Language Interventions	Speech or language issues/interventions. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Psychomotor Interventions	Psychomotor issues/interventions. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants With Global Developmental Delay	Child has global developmental delay. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants With Attention Deficit Hyperactivity Disorder	Child has been diagnosed with Attention Deficit Hyperactivity Disorder. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants With Autism Spectrum Disorder	Child has been diagnosis with Autism Spectrum Disorder. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants With a Hearing Abnormality	Child has a hearing abnormality. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants With a Visual Defect in Either Eye	Child has a visual defect in either eye. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants With a Hearing Aid	Child has a hearing aid. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants Who Are Legally Blind	Child is legally blind. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Number of Participants Who Have Cerebral Palsy	Child has cerebral palsy. These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Parents' Awareness of Group Allocation	Whether or not a parent is aware of which treatment group their child was allocated to. This variable will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Awareness of Group Allocation by Psychologist	These variables will be summarised using descriptive statistics by treatment arm only. No treatment effect or confidence intervals will be calculated.	At 5 years chronological age
Awareness of Group Allocation by Pediatrician		At 5 years chronological age

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: Food and Drug Administration (FDA); Royal Children's Hospital; Murdoch Childrens Research Institute; Royal Hospital for Sick Children
• Investigators: Principal Investigator: Andrew Davidson, MD, Royal Children's Hospital, Victoria, Australia; Principal Investigator: Mary Ellen McCann, MD, Children's Hospital Boston, United States of America; Principal Investigator: Neil Morton, MD, Royal Hospital for Sick Children, Glasgow, United Kingdom

Publications and helpful links

General Publications

• Davidson A, McCann ME, Morton N. Anesthesia neurotoxicity in neonates: the need for clinical research. Anesth Analg. 2007 Sep;105(3):881-2. doi: 10.1213/01.ane.0000269692.57331.48. No abstract available.
• McCann ME, de Graaff JC, Dorris L, Disma N, Withington D, Bell G, Grobler A, Stargatt R, Hunt RW, Sheppard SJ, Marmor J, Giribaldi G, Bellinger DC, Hartmann PL, Hardy P, Frawley G, Izzo F, von Ungern Sternberg BS, Lynn A, Wilton N, Mueller M, Polaner DM, Absalom AR, Szmuk P, Morton N, Berde C, Soriano S, Davidson AJ; GAS Consortium. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019 Feb 16;393(10172):664-677. doi: 10.1016/S0140-6736(18)32485-1. Epub 2019 Feb 14. Erratum In: Lancet. 2019 Aug 24;394(10199):638.
• 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; GAS consortium. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016 Jan 16;387(10015):239-50. doi: 10.1016/S0140-6736(15)00608-X. Epub 2015 Nov 4. Erratum In: Lancet. 2016 Jan 16;387(10015):228.

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2006
• Primary Completion (Actual): June 30, 2018
• Study Completion (Actual): June 30, 2018

Study Registration Dates

• First Submitted: September 18, 2008
• First Submitted That Met QC Criteria: September 19, 2008
• First Posted (Estimate): September 22, 2008

Study Record Updates

• Last Update Posted (Actual): April 29, 2020
• Last Update Submitted That Met QC Criteria: April 16, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Infants; bilateral; unilateral; repair; scheduled
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Hernia, Abdominal; Hernia; Hernia, Inguinal; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics
• Other Study ID Numbers: 06-07-0320

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes