Abstract: We included 15 studies. The total number of participants included in the analyses was 3520. Most studies were small with fewer than 120 participants, although two larger studies with 2012 and 671 participants were included. There was considerable variation in many of the study characteristics, including the anaesthetics used. The concentrations of nitrous oxide varied between 50% and 70%, and half of the studies used clinical signs and haemodynamic changes to monitor depth of anaesthesia. As it was not possible to blind the anaesthetist to the anaesthetic used, we rated all studies at high risk of performance bias and we therefore downgraded the quality of evidence by one level for risk of bias using the GRADE approach. Other types of bias were generally low, or were rated unclear due to missing information. No studies were designed to measure AAGA as the primary outcome, and were therefore statistically underpowered to answer this review question. Despite the inclusion of 3520 participants, only three awareness events were reported by two studies. In one study the event was due to technical failure. Due to the rarity of the events, we did not consider it appropriate to pool the data, and we therefore downgraded the quality of evidence by a further level for imprecision using GRADE. It is not possible to draw any conclusions from this review. The included studies were mainly small (fewer than 120 participants) and there were limited estimates of effect, with only two studies reporting any events. We cannot therefore determine whether the use of nitrous oxide in general anaesthesia increases, decreases or has no effect on the risk of accidental awareness.

Plain-language summary: We included 15 studies. The studies covered 3520 people. Although most studies were small with fewer than 120 participants, there were two larger studies with 2012 and 671 participants included. There was a great variation in many of the important elements among the studies, including the type of anaesthetics used and the levels of nitrous oxide used. No study was designed to measure accidental awareness, but rather they measured it as a secondary outcome. Although there were 3520 participants included in the studies, there were only three reports of a participant becoming aware. These were reported in two studies, and one was thought to be due to an error in the anaesthetic procedure. Nine studies reported where the funds for the research were obtained. Two were funded by pharmaceutical companies, suggesting a potential bias, whereas five were funded through Universities or Government health research grants or a charity, limiting the risk of bias. The remaining two studies reported that there was no conflict of interest, also reducing the risk of bias in these studies. Due to safety issues, all of the anaesthetists had to know what anaesthesia was being used. However, this means that the study results may have been biased. Other indicators suggested a low risk of bias, or an unclear risk because of missing information. The quality of the evidence is also low due to the lack of reports of a participant becoming aware. It is not possible to draw any conclusions from this review. The included studies were mainly too small, and only two studies reported any events. The review question is inadequately supported by the lack of strong evidence. The effect of nitrous oxide is hardly observed due to the small sample size.