Clinical trial NCT00756600
Conditions: Inguinal Hernia
Keywords: Infants scheduled unilateral bilateral repair
Sponsor: Boston Children's Hospital
Start date: 2006-10-23; Completion date: 2018-06-30
Enrollment: 643 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: Regional Anesthesia arm 2: General Anesthesia
Interventions: intervention 1: Regional Anesthesia intervention 2: General Anesthesia
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
A Multi-site Randomized Controlled Trial Comparing Regional and General Anesthesia 
for Effects on Neurodevelopmental Outcome and Apnea in Infants 
 
Document date: February 27th, 2020 
NCT identifier: NCT00756600 
Publication: Neurodevelopmental outcome at 5 years of age after general anaesthesia or 
awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, 
controlled equivalence trial  (February, 2019) 
 
Experimental Design and Methods: 
We did a multicentre, international, parallel-group, randomised, assessor-masked, controlled, 
equivalence trial comparing neurodevelopmental outcome at age 5 years, in infants randomised 
to receive awake-regional anaesthesia or general anaesthesia for inguinal herniorrhaphy. The 
trial was done at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and 
New Zealand. Institutional review board or human research ethics committee approval was 
obtained at each site, and written informed consent was obtained from the infant's parents or 
guardians. A summary of the protocol is available online.21 
Infants were included if they were aged 60 weeks' postmenstrual age or less, born at greater 
than 26 weeks' gestation, and scheduled for inguinal herniorrhaphy. Exclusion criteria were any 
contraindication for either anaesthetic technique used in the study, a history of congenital heart 
disease requiring surgery or pharmacotherapy, mechanical ventilation immediately before 
surgery, known chromosomal abnormalities or other known acquired or congenital abnormalities 
that might affect neurodevelopment, previous exposure to volatile general anaesthesia or 
benzodiazepines as a neonate or in the third trimester in utero, any known neurological injury 
such as cystic periventricular leukomalacia or grade three or four intraventricular haemorrhage, 
any social or geographical factor that might make follow-up difficult, or having a primary 
language at home in a region where neurodevelopmental tests were not available in that 
language. We identified eligible infants from operating room schedules or at preadmission 
clinics and recruited in the clinic or in the preadmission areas of the operating floor. 
Randomisation and masking 


Infants were randomly assigned (1:1) to receive either general anaesthesia or awake-regional 
anaesthesia using a 24-h web-based randomisation service managed by the Data Management 
and Analysis Centre, Department of Public Health, University of Adelaide, Australia. 
Randomisation was done in blocks of two or four in a computer-generated random-allocation 
sequence, with stratification by site and by gestational age at birth (26 weeks to 29 weeks and 6 
days, 30 weeks to 36 weeks and 6 days, and 37 weeks or more). The anaesthetist was aware 
of group allocation, but individuals who administered the neurodevelopmental assessments 
were not. Parents who asked about their infant's group allocation were informed and told to 
mask this information from assessors. After assessments were completed, parents and 
assessors were asked if they were aware of group allocation. 
Procedures 
The awake-regional group received a spinal, caudal, or combined caudal and spinal 
anaesthetic, according to institutional preferences. Bupivacaine or levobupivacaine at a dose of 
0·75–1 mg/kg was administered for spinal anaesthesia. Caudal anaesthesia was with 0·25% 
bupivacaine or levobupivacaine up to a total dose of 2·5 mg/kg. In the USA, several patients in 
whom it was known that the surgery would take longer than 1 h were also administered 3% 
chloroprocaine via a caudal catheter (loading bolus of 3% chloroprocaine 1 mL/kg over several 
minutes and then an infusion at 1–2 mL/kg per h). Additional ilioinguinal and field blocks were 
used according to surgical preference. Oral sucrose was given if the child was unsettled, but no 
other pharmacological sedation was permitted. Infants who showed agitation that was not 
resolved by oral sucrose, or in whom the awake-regional anaesthetic was inadequate, were 
treated with sevoflurane. The administration of sevoflurane, nitrous oxide, or any other general 
anaesthetic in this group was considered a protocol violation. 
The general anaesthesia group received sevoflurane for induction and maintenance in a mix of 
air and oxygen. The concentration of sevoflurane, choice of airway device, ventilation technique, 
and use of neuromuscular blocking agents were left to the preference of the anaesthetist. 
Supplemental opioids and nitrous oxide were not allowed, but caudal, ilioinguinal–
iliohypogastric, or field blocks with bupivacaine were permitted to provide postoperative 
analgesia. 
Both groups could also be given oral, rectal, or intravenous paracetamol. Monitoring and 
recording were identical in both groups, with heart rate, blood pressure, oxygen saturation, and 
expired sevoflurane concentrations (where applicable) every 5 min. In both groups, 


intraoperative serum glucose values were measured after induction, and rescue protocols for 
hypoglycaemia, hypotension, and hypoxaemia were applied as appropriate. 
Outcomes 
The primary outcome measure was the Wechsler Preschool and Primary Scale of Intelligence, 
third edition (WPPSI-III) full-scale intelligence quotient (FSIQ) score. Secondary outcome 
measures were selected NEPSY-II subtests to assess attention and executive function; the 
Wechsler Individual Achievement Test, second edition (WIAT-II), or the BVN (the Italian 
equivalent of the WIAT-II); selected subtests of the Children's Memory Scale (CMS); the global 
executive composite of the Behaviour Rating Inventory of Executive Function, Preschool version 
(BRIEF-P); the Adaptive Behaviour Assessment System, second edition (ABAS-II); and the 
Child Behaviour Checklist caregiver questionnaire (CBCL). Neuropsychological assessments 
were to be done within 4 months of the child turning 5 years of age. The total assessment time 
was estimated to take around 3 h to complete, and assessments were done at each site by a 
child psychologist certified to conduct the tests. Quality control was maintained by a national 
coordinating psychologist. Participatory tests were administered by the psychologist, and a 
parent or caregiver completed the informant report questionnaires. Parents were asked if their 
child had been diagnosed with cerebral palsy, autism spectrum disorder, or attention-deficit 
hyperactivity disorder (ADHD), or had any other neurodevelopmental issues. They were also 
asked if the child had received any neurodevelopmental interventions. Hearing or vision 
problems were also noted. Demographic data, family structure, and medical history since 
randomisation were recorded, and a brief physical and neurological examination was done for 
each patient. All these outcome measures were prespecified in the protocol. 
All study data were sent to the Murdoch Children's Research Institute in Melbourne, Australia. 
All data forms were checked by a research assistant not involved in primary data collection or 
entry. Data on test forms that were not completed according to test manual instructions were 
rejected. 
An independent data safety monitoring committee met around every 6 months during 
recruitment. Site visits were done by the national coordinating teams for each country annually 
or biennially, and site visits at the national coordinating sites were done by principal 
investigators from other nations to check the validity of data. Summary data by allocation were 
presented to this committee. 
 


Statistical Analysis Plan: 
The study hypothesis was that WPPSI-III FSIQ score at age 5 years is equivalent in infants who 
have received awake-regional anaesthesia or general anaesthesia for inguinal herniorrhaphy. 
Because this was an equivalence study, the outcome was analysed on an per-protocol basis to 
ensure a conservative estimate of the treatment effect in the direction of non-equivalence. 
Although it is best practice to analyse outcomes on an intention-to-treat basis, there were 
unavoidable protocol violations in this study (the majority of which were in babies allocated to 
receive regional anaesthesia who had some exposure to general anaesthesia, particularly if the 
awake-regional anaesthesia failed). If all infants were analysed on an intention-to-treat basis, 
this switching from one randomised treatment to the other could dilute the potential effect of 
general anaesthesia and thus bias the trial towards equivalence.22 
Equivalence was defined a priori as the 95% CI of the difference in means of the FSIQ lying 
within −5 and +5 IQ points. Intention-to-treat analyses were also planned. All CIs are two-sided. 
The sample size was based on the primary outcome. Assuming an expected difference of 1 
standardised score point, a standard deviation of 15, and a 90% chance that a 95% CI will 
exclude a difference of more than 5 points (the largest difference acceptable to show 
equivalence), the trial would need 598 infants. The sample size formula used was based on 
approximations to the normal distribution, and used a two one-sided test procedure. Enrolling 
roughly 720 participants would allow for 10% loss to follow-up and 10% with a major protocol 
violation. 
We used multiple imputation under a multivariate normal distribution to impute missing outcome 
data in the primary analysis of all outcomes, with a sensitivity analysis done on only complete 
cases. Multiple imputations were done with the mi impute mvn statement in Stata (version 14.2). 
The variables used in the multiple imputation models included baseline, post-randomisation, 2-
year cognitive variables, and 5-year outcome variables. A number of prespecified variables 
were used as possible predictor variables within the imputation approach, including baseline 
variables (anaesthesia group, country, sex, gestational age at birth, birthweight, antenatal 
steroids received by mother, mother's education, and maternal age <21 years), variables at 
surgery (need for fluid bolus for hypotension, duration of surgery, significant postoperative 
apnoea, and age), variables at age 2 years (composite cognitive, language, motor and social–
emotional score on the Bayley Scales of Infant and Toddler Development, third edition; any 
additional anaesthetic exposures since the inguinal herniorrhaphy; any interventions for 
neurodevelopmental problems; and any other neurological abnormality), and variables at age 5 


years (WPPSI-III FSIQ, any chronic illness, any additional anaesthetic exposures since the 
inguinal herniorrhaphy, total length of any readmission to hospital, cerebral palsy, any 
interventions for neurodevelopmental problems, and any other neurological abnormality). Since 
most of these variables also have missingness, they were also imputed where necessary. With 
many missing observations, these multiple imputation models did not always converge, in which 
case, to ensure convergence of models, applicable variables were not included. The variables 
used in the analysis model were always included in the imputation models. 
For all continuous outcomes, linear regression was used with the factor variables anaesthesia 
group (awake-regional anaesthesia and general anaesthesia), with gestational age at birth and 
country as fixed effects. Adjusted mean differences are presented with 95% CIs. 
All binary outcomes were analysed with generalised linear models with binomial link function to 
enable estimation of risk ratios, adjusting for the same factors as for the linear regression. Risk 
ratios are presented with 95% CIs. 
The following subgroup analyses were prespecified in the statistical analysis plan: country, 
duration of surgery (≥120 min or <120 min), and age at surgery (>70 days or ≤70 days). A 
subgroup analysis by ex-term versus ex-preterm (born at <37 weeks' gestation) was also done 
post hoc. p values for the interactions are shown along with subgroup treatment effect estimates 
and 95% CIs. All analyses were done in Stata (version 14.2). 
The GAS trial is registered in Australia and New Zealand at ANZCTR (number 
ACTRN12606000441516, first registered Oct 16, 2006); in the USA at ClinicalTrials.gov 
(number NCT00756600, first registered on Sept 18, 2008); and in the UK at UK Clinical 
Research Network (number 6635; ISRCTN ID 12437565; MREC number 07/S0709/20). The 
statistical analysis plan is available at ANZCTR (number ACTRN12606000441516).23