Abstract: We included 52 studies with 41,331 participants; two studies were quasi-randomized and the remaining studies were RCTs. All studies included participants undergoing surgery under general anaesthesia. Three studies recruited only participants who were at high risk of intraoperative awareness, whilst two studies specifically recruited an unselected participant group. We analysed the data according to two comparison groups: BIS versus clinical signs; and BIS versus ETAG. Forty-eight studies used clinical signs as a comparison method, which included titration of anaesthesia according to criteria such as blood pressure or heart rate and, six studies used ETAG to guide anaesthesia. Whilst BIS target values differed between studies, all were within a range of values between 40 to 60. BIS versus clinical signs We found low-certainty evidence that BIS-guided anaesthesia may reduce the risk of intraoperative awareness in a surgical population that were unselected or at high risk of awareness (Peto odds ratio (OR) 0.36, 95% CI 0.21 to 0.60; I2 = 61%; 27 studies; 9765 participants). However, events were rare with only five of 27 studies with reported incidences; we found that incidences of intraoperative awareness when BIS was used were three per 1000 (95% CI 2 to 6 per 1000) compared to nine per 1000 when anaesthesia was guided by clinical signs. Of the five studies with event data, one included participants at high risk of awareness and one included unselected participants, four used a structured questionnaire for assessment, and two used an adjudication process to identify confirmed or definite awareness. Early recovery times were also improved when BIS was used. We found low-certainty evidence that BIS may reduce the time to eye opening by mean difference (MD) 1.78 minutes (95% CI -2.53 to -1.03 minutes; 22 studies; 1494 participants), the time to orientation by MD 3.18 minutes (95% CI -4.03 to -2.33 minutes; 6 studies; 273 participants), and the time to discharge from the postanaesthesia care unit (PACU) by MD 6.86 minutes (95% CI -11.72 to -2 minutes; 13 studies; 930 participants). BIS versus ETAG Again, events of intraoperative awareness were extremely rare, and we found no evidence of a difference in incidences of intraoperative awareness according to whether anaesthesia was guided by BIS or by ETAG in a surgical population at unselected or at high risk of awareness (Peto OR 1.13, 95% CI 0.56 to 2.26; I2 = 37%; 5 studies; 26,572 participants; low-certainty evidence). Incidences of intraoperative awareness were one per 1000 in both groups. Only three of five studies reported events, two included participants at high risk of awareness and one included unselected participants, all used a structured questionnaire for assessment and an adjudication process to identify confirmed or definite awareness. One large study (9376 participants) reported a reduced time to discharge from the PACU by a median of three minutes less, and we judged the certainty of this evidence to be low. No studies measured or reported the time to eye opening and the time to orientation. Certainty of the evidence We used GRADE to downgrade the evidence for all outcomes to low certainty. The incidence of intraoperative awareness is so infrequent such that, despite the inclusion of some large multi-centre studies in analyses, we believed that the effect estimates were imprecise. In addition, analyses included studies that we judged to have limitations owing to some assessments of high or unclear bias and in all studies, it was not possible to blind anaesthetists to the different methods of monitoring depth of anaesthesia. Studies often did not report a clear definition of intraoperative awareness. Time points of measurement differed, and methods used to identify intraoperative awareness also differed and we expected that some assessment tools were more comprehensive than others. Intraoperative awareness is infrequent and, despite identifying a large number of eligible studies, evidence for the effectiveness of using BIS to guide anaesthetic depth is imprecise. We found that BIS-guided anaesthesia compared to clinical signs may reduce the risk of intraoperative awareness and improve early recovery times in people undergoing surgery under general anaesthesia but we found no evidence of a difference between BIS-guided anaesthesia and ETAG-guided anaesthesia. We found six studies awaiting classification and two ongoing studies; inclusion of these studies in future updates may increase the certainty of the evidence.

Plain-language summary: The evidence is current to 26 March 2019. We found 52 studies with 41,331 participants. Six studies are awaiting classification (because we did not have sufficient information to assess them), and two studies are ongoing. All studies included people having surgery under general anaesthesia. Three studies included only people who were at high risk of intraoperative awareness, and two studies included only people who were not selected according to high risk of intraoperative awareness. Forty-eight studies compared BIS-guided anaesthesia with anaesthesia guided by clinical signs, and six studies compared BIS-guided anaesthesia with ETAG-guided anaesthesia. We found low-certainty evidence that BIS-guided anaesthesia may reduce the risk of intraoperative awareness. However, events were rare and only five of 27 studies reported incidences. When BIS-guided anaesthesia was used, we found three per 1000 fewer incidences of intraoperative awareness compared to nine per 1000 incidences when anaesthesia was guided by clinical signs. In addition, we found low-certainty evidence that BIS may improve recovery - the time for people to open their eyes was less, as was the time for orientation, and the time to be discharged from the post-anaesthesia care unit. We found no evidence of a difference in incidences of intraoperative awareness according to whether anaesthesia was guided by BIS or by ETAG, although, again, there were few incidences of awareness (1 per 1000 in each group). Only one study that compared BIS with ETAG-guided anaesthesia measured recovery times; this low-certainty evidence showed that discharge from the postanaesthesia care unit was earlier if anaesthesia was BIS-guided. No studies that compared BIS with ETAG-guided anaesthesia measured the time to eye opening or the time to orientation. We used GRADE to downgrade the evidence for all outcomes to low certainty. The incidence of intraoperative awareness is so rare and, even though we found some large studies, we concluded that the evidence was still imprecise. In addition, we judged many studies to have limitations because of high or unclear risks of bias. For example, all of the anaesthetists were aware of using an additional BIS monitor and we could not be certain how this affected the anaesthetists' standard practice. In addition, we noted that some studies did not report a clear definition of intraoperative awareness. Time points of measurement differed, and the methods used to identify intraoperative awareness also differed and we expected that some assessment tools were more comprehensive than others. Intraoperative awareness is rare, and despite finding a large number of eligible studies, evidence for the effectiveness of using BIS to guide anaesthetic depth is imprecise. We found low-certainty evidence that BIS-guided anaesthesia compared to anaesthesia guided by clinical signs may reduce the risk of intraoperative awareness and improve early recovery times in people having surgery under general anaesthesia. We found no evidence of a difference between BIS-guided anaesthesia and ETAG-guided anaesthesia, and we also judged this evidence to be low certainty.