We reviewed the evidence about the effect of nitrous oxide used as part of a general anaesthesia on the risk of accidental awareness during anaesthesia in people over the age of five years undergoing surgery.
Accidental awareness during general anaesthetic is when a person accidentally becomes conscious during surgery, performed with general anaesthesia, and can remember the event once they have woken up. Accidental awareness is an uncommon event, but it can be extremely distressing for the patient and the doctors. There is some evidence suggesting that use of nitrous oxide may increase the risk of accidental awareness. However, the literature is contradictory, with some studies finding no difference and others a decreased risk of awareness in persons anaesthetized with nitrous oxide.
We searched for studies in December 2015.
Study characteristics and key results
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.
Quality of the evidence
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.
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.
Accidental awareness during general anaesthesia (AAGA) is when a patient unintentionally becomes conscious during a procedure performed with general anaesthesia and subsequently has explicit recall of this event. Incidence estimates for AAGA vary, with the most common estimate being one to two cases per 1000 general anaesthetics. Evidence linking nitrous oxide use and an increased risk of AAGA has come from observational studies data but the literature is contradictory, with some studies finding a protective effect of nitrous oxide.
To assess the effect of general anaesthesia including nitrous oxide on the risk of AAGA in patients aged five years and over.
We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and trial registers ((www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/network/en/) and Current Controlled Trials (www.isrctn.com/)) for eligible studies on December 9 2015. In addition, we conducted forward and backward citation searching using key identified papers.
We considered all randomized controlled trials (RCTs), including quasi-randomized studies and cluster-randomized studies, of participants aged five years or older receiving general anaesthesia for any type of surgery.
We included trials in which participants receiving general anaesthesia that included nitrous oxide for maintenance at a concentration of at least 30% were compared with participants receiving no nitrous oxide during general anaesthesia. The intervention group must have received nitrous oxide in conjunction with an additional anaesthetic. We excluded studies where the depth of anaesthesia differed between the study arms. For inclusion in the review, studies needed to state in their methods that they planned to assess AAGA. We defined this as when a patient becomes conscious during a procedure performed with general anaesthesia and subsequently has explicit recall of this event.
We used standard methodological procedures expected by Cochrane to identify studies. We extracted data and conducted 'Risk of bias' assessment using the Covidence database.
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.