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


Animal models have demonstrated that substantial exposure to general anaesthetic agents may lead to neurotoxicity such as neuronal cell death, abnormal behaviour and impaired cognition.  Retrospective cohort studies in children have so far been inconclusive.  This study is the first prospective clinical trial to assess the effects of anaesthesia on neurodevelopment in humans.

This is a RCT of 722 infants undergoing inguinal hernia repair.  Patients were allocated to either:

  • Regional / awake anaesthesia (n = 363) – either spinal, caudal or combined caudal + spinal
  • General anaesthesia (n = 359) – sevoflurane induction with sevo / O2 / air maintenance; no supplemental opioids or N20; asleep caudal or ilioinguinal / iliohypogastric blocks permitted

Primary Outcome:

  • Wechsler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III) full-scale intelligence quotient (FSIQ) score performed within four months of the child turning five

Secondary Outcome:

  • Interim analysis performed at age two – published previously (Lancet 2016; 387: 239–50)
  • Diagnosis of cerebral palsy, autism spectrum disorder or attention deficit hyperactivity disorder, or any other neurodevelopmental issues requiring intervention
  • Hearing or vision problems, brief physical and neurological assessment


  • Inguinal hernia repair occurs predominantly in boys resulting in a sex biased study population, its generalisability to girls is unclear.
  • The duration of exposure was short (most under one hour) and in early infancy. It is not clear what age group is most vulnerable, nor the effect of longer or repeated exposures.
  • Some of the study population had subsequent anaesthetics, however these cases were balanced between the two groups and considered unlikely to have biased the results.
  • The general anaesthesia group received sevoflurane only and did not receive other commonly utilised general anaesthetic agents such as propofol, desflurane or isoflurane. The effect of these agents on neurodevelopment has not been determined.
  • Cognitive and neurodevelopmental function at age 5 has been shown to correlate with adult cognitive function. However, several executive functions and social and emotional skills do not develop until later in childhood and could not be examined in this study.

Take home message:

A single general anaesthetic with sevoflurane for surgery in early infancy does not appear to alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia.  This should be taken in the context of a predominantly male population and short exposure duration.

Reviewed by Shannon Morrison (RCH Fellow)