Jurgen De Graaff | Wilhelmina Children’s Hospital, UMC Utrecht, The Netherlands
Nicola Disma | Istituto Giannina Gaslini, Genoa, Italy
The GAS-study is the first international multicentre randomized trial looking at the effects of anaesthesia in infants on long-term development of the brain. Recently, some secondary outcomes from the GAS-study have been published in three articles: the first two papers relate to post-op apnoea and on success of spinal anaesthesia, the third reports the neurodevelopmental outcomes at 2–years-of-age.
There has been growing concern about the safety of virtually all general anaesthetics in young children. This concern is based on studies in animals demonstrating long-term brain injury caused by exposure to anaesthetics during the early stages of brain development. Histological injuries in the brain corresponded to abnormalities in behaviour, learning, and memory in mice, rats, and even non-human primates. Thus far, the clinical research on this important phenomenon was limited to mostly retrospective cohort studies with conflicting results. Epidemiological studies are likely influenced by confounding that cannot be eliminated. Results can only demonstrate association and not causation. A randomized clinical trial comparing general to regional anaesthesia without sedatives was best plausible research design.
In 2006 researchers in Australia, the Unites States, Canada, New Zealand, and Europe (Italy, UK, and the Netherlands) joined to develop such a trial: the “GAS-study”. The study design randomized patients with a postmenstrual age of 60 weeks or less, requiring surgery for inguinal hernia, to receive general anaesthesia (GA) in combination with a caudal block or a sole regional anaesthesia (RA, spinal, and/or caudal without any sedation or general anaesthesia). The primary objective was to determine whether regional and general anaesthesia result in equivalent neurodevelopmental outcomes at 5–years-of-age. Secondary objectives were to assess the neurological outcome at 2–years-of-age, the frequency and characteristics of apnoea, and factors for failure of regional anaesthesia.
Between 2007 and 2013, 712 patients in 28 sites were randomized for GA or RA. In the RA arm, 70 (17%) patients had supplemental anaesthesia or sedation, so 286 patients in RA arm and 356 patients in the GA arm were available for the as per protocol analyses (APP).
The first published paper describes the results from the apnoea outcome, showing no differences in overall risk of apnoea between GA and RA in the first 12 hours (APP analyses: OR 0.47; 95% CI 0.17–1.32, P = 0.15).1 In subgroup analyses, RA reduced the risk of early postoperative apnoea (0–30 min APP analyses: OR 0.07; 95% CI, 0.01–0.84; P = 0.0359) and the risk for needing a significant intervention for apnoea (OR 0.25; 95% CI, 0.11–0.57; P = 0.0009), but not the risk of late apnoea (30 min–12h APP analyses: OR 1.46; 95% CI: 0.52–4.12; P = 0.47).
The second paper describes the success rate of locoregional anaesthesia for hernia repair. Spinal alone was sufficient in 87% of the cases and combined spinal caudal anaesthesia (CSCA) in 76% of the cases.2 The RA failed completely (conversion to GA) in 10% of the cases, and in 7% some supplemental sedation was required. Unfortunately, risk factors for failure of RA could not be identified; gestational age, age at surgery, weight at surgery, drugs used, anaesthetic technique, and experience of the anaesthetist were not predictive for success of RA.
Lastly, the results of the interim analyses of the follow-up of the patients at age 2 years have been reported in the Lancet.3 A standardized international test to evaluate the psychomotor development (Bayley-III) at 2 years did not show any difference between the groups of children who received RA or GA. The composite cognitive score in the group of children who received RA was 98.6 (SD: 14.2) and in those who received GA was 98.2 (SD: 14.7). An important limitation of this result is that the psychomotor and cognitive functions at an age of two years is not a very accurate measure, as the brain is still under development and not all the cognitive domains can be properly investigated. Furthermore, the duration of anaesthesia was only just under one hour (54 minutes), which means that the effects of longer anaesthesia still need to be investigated. Nevertheless, these results from the GAS-study are a strong indication that a 1-hour sevoflurane-based anaesthesia does not increase the risk of an adverse neurological outcome at the age of 2 years. Thus far, this is the first and most convincing clinical evidence that general anaesthesia in infancy causes no major neurological damage.