Incidence apart, previous studies have addressed risk factors for AAGA. Certain types of surgery (e.g. cardiac, obstetric), female sex 21 , 22 , higher ASA physical status 21 , 23 , 24 and obesity 25 - 27 are all implicated. The notion of an intrinsic, possibly genetic, resistance to anaesthesia has also been raised, with up to 11% of patients with AAGA having a previous history 8 , 27 and an important minority of AAGA cases having no apparent cause 9 , 28 .

The NAP5 Baseline Survey reported an incidence for patient reports of AAGA of approximately 1:15 000, similar to the findings of Pollard et al. 16 . A similar survey conducted in Ireland, using as denominator an estimate of anaesthetic activity that was conducted in parallel 18 , reported a similarly low incidence (1:23 000) 19 . These surveys suffer from potential limitations, including failure of patients to report the event, memory of the anaesthetist for the incident, bias, and also possible systems failures reventing the anaesthetist's being made aware of the report 20 .

Perhaps the most common tool used to establish the incidence of AAGA has been the Brice interview, conducted immediately after anaesthesia, and often repeated up to three times over up to a month 6 . Over several decades, the incidence appears to have consistently reported to be approximately 1–2:1000 general anaesthetics 7 - 12 . It has been reported to be higher in obstetric (1:384 13 ), cardiac (1:43 14 ), and paediatric (1:135 15 ) anaesthesia. However, some studies do report a much lower incidence (1:14 560 16 ), but these have been criticised for using a modified Brice interview within 48 h of anaesthesia and not repeating it 17 .

The 5th National Audit Project (NAP5) of the Royal College of Anaesthetists (RCoA) and the Association of Anaesthetists of Great Britain and Ireland (AAGBI) concerned accidental awareness during general anaesthesia (AAGA). It commenced its phase of prospective data collection on 1 June 2012 and completed it on 31 May 2013 1 - 3 . Two of its stated aims included estimating an incidence of reports of AAGA and determining risk factors. The methodology is described in an accompanying paper 4 and together with its activity survey 5 , makes NAP5 the largest and most comprehensive study on AAGA and its risk factors ever undertaken.

The methods are described in the accompanying paper 4 . For the analysis of risk factors, we compared the relative frequencies of features in AAGA reports with the frequency of those in the NAP5 activity survey 5 . Psychological aspects, the impact of human factors, quality of care and preventability, cases arising after sedation, and issues of consent and medicolegal aspects are discussed in a separate paper 29 . Data are quoted with 95% Poisson confidence intervals 30 , and chi‐squared testing reserved for some comparisons of certain/probable AAGA frequencies (the most complete dataset).

There was a striking difference between the incidences of AAGA when no neuromuscular blocking drug was used (1:135 900) compared to when one was used (1:8200). The latter figure was very similar to the incidence for cardiothoracic surgery, where use of neuromuscular blocking drug is commonplace, which might explain over‐representation of this specialty in AAGA cases (Fig. 2 ). Another subgroup where neuromuscular blocking drugs are commonly used with notably high incidence is obstetrics (1:670). The estimate for AAGA in children (where the activity survey indicates neuromuscular blocking drugs were less often used), on the other hand, was very low.

The most pessimistic incidence of patient reports of suspected AAGA can be estimated assuming that all 471 original requests for logins were made on some positive grounds. This would give an overall incidence of no higher than 1:6000 (95% CI 1:5370–6450).

The activity survey indicated that there were approximately 2 800 000 cases of general anaesthesia in the year studied. Several incidences can be calculated depending on which types of cases are included or not included (Table 2 ). We discounted the sedation cases (an incidence for which is given in an accompanying paper 29 ), unassessable and unlikely reports, and the statement‐only cases, but included the drug‐swap cases and those in the intensive care unit (ICU), which left 167 cases. This yielded an incidence of patient reports of AAGA approximately 1:17 000 (95% CI 1:14 300–19 500) general anaesthetics. If drug swaps (leading to brief awake paralysis but actually occurring before anaesthesia) were not studied, we were left with 147 cases and an incidence of 1:18 800 (95% CI 1:16 000–22 300). The incidence of certain/probable and possible accidental awareness cases was ~1:19 600 anaesthetics (95% CI 1:16 700–23 450). Both the number and the estimated incidence was remarkably close to the estimate from the NAP5 baseline survey of 153 cases and 1:15 000, respectively 2 . If we had included all unassessable and statement‐only cases as if they were also accurate reports of AAGA, then this gives a ‘pessimistic incidence’ of 1:12 000 (95% CI 1:10 600–13 760).

An analysis of the 110 certain/probable reports of AAGA (those with the most complete dataset) identified the following additional factors as also being over‐represented: out‐of‐hours operating (p < 0.0001); urgent/emergency surgery (p < 0.0001); and junior staff (p = 0.003). The following factors were not associated with AAGA; race (p = 0.42); ASA physical status (p = 0.23); and use of nitrous oxide (p = 0.26).

Of the maintenance agents, the volatile anaesthetic agents appeared in AAGA cases in broad proportion to their general use, although sevoflurane was somewhat under‐represented. Total intravenous anaesthesia (TIVA), including all methods of administration, appeared over‐represented (18% in AAGA cases, but 8% overall; a greater than twofold difference).

Of the anaesthetic induction agents, thiopental, etomidate, midazolam and ketamine were over‐represented in AAGA cases. Thiopental was used in only 3% of anaesthetic inductions, but was implicated in 23% of AAGA reports; an almost eightfold difference. Fewer cases, overall, were conducted with the other three agents, making them subject to greater variation in estimates, so these data should be interpreted with caution.

Neuromuscular blockade appeared far more commonly in the AAGA reports (93% of reports) than its use in the activity survey (46% of anaesthetics). Notably, a nerve stimulator was used after a nondepolarising neuromuscular blocking drug had been administered much less frequently in AAGA cases (9%) compared with the activity survey (38%). Similarly, reversal of nondepolarising neuromuscular blocking drugs was less common in AAGA cases (48%) than in the activity survey (68%). Thus, the combination of using neuromuscular blocking drugs, not monitoring their effect, and not reversing it, seemed to incur a risk for AAGA.

Representation of some components of anaesthesia practice in certain/probable and possible accidental awareness during general anaesthesia reports (bars) compared with distribution in the activity survey (dots and lines). Propofol in first bar refers to its use as an induction agent, as distinct from a later bar (TIVA) where its use is referred to for maintenance. TIVA, total intravenous anaesthesia; TCI, target‐controlled infusion; N 2 O, nitrous oxide; RSI, rapid sequence induction; NMB, neuromuscular blockade; DOA, specific depth of anaesthesia monitor.

Two thirds of certain/probable and possible reports were related to the dynamic phases of anaesthesia: induction of anaesthesia (59 (47%)) and emergence (23 (18%)), compared with during maintenance (43 (34%)). In nine cases, AAGA was judged to occur during multiple phases, and in seven cases, the panel was unable to judge.

Certain/probable and possible accidental awareness during general anaesthesia cases by specialty (bars) compared with distribution in the activity survey (dots and line). Three cases in bariatric and transplant surgery have been omitted as they were not specified in the activity survey. ENT, ear, nose, throat; maxfax, maxillofacial surgery; ortho, orthopaedic surgery; eye, ophthalmology; X‐ray, radiology; general surgery includes urology and other specialties not listed.

A total of 300 reports of AAGA were made to NAP5 in the reporting period 1 June 2012 to 31 May 2013, of which 141 (47%) were considered to be certain/probable or possible (Table 1 ; see accompanying paper for categorisation of AAGA reports 4 ). There was a marked under‐representation of children, a slight over‐representation of younger/middle‐aged adults, and an under‐representation of the elderly (Fig. 1 a). There was also a preponderance of women (91, 65%). Over three times as many obese patients experienced AAGA than generally undergo anaesthesia (Fig. 1 b), but ASA grades were equivalently represented (Fig. 1 c).

Discussion

Our main finding was that, similar to that of the NAP5 baseline surveys 2, 19, the overall incidence of patient reports of AAGA was very low, approximately 1 in 19 000 general anaesthetics. Even the most pessimistic estimate was 1 in 6000. We believe this is important new information for anaesthetists and patients.

Of note, these figures are several orders of magnitude less common than the incidence consistently ascertained using the Brice interview, which may be as high as 1:600 7-12. If we assume the Brice method to reveal the correct incidence, then it means that for every 40 patients who experience AAGA by Brice, just one will make a report, according to our data. The reasons for this marked disparity need fuller discussion. Methodological differences may be relevant, including inherent weaknesses in the Brice interview, vs weaknesses in the process of NAP5 data collection. The differences may also relate to the possible impact the AAGA had on the patient. The theoretical reasons for not reporting an experience are diametrically opposed: either because it was so trivial that it simply does not warrant a report; or because the event was so traumatic that it is difficult or impossible to make a report.

Some support for the first interpretation may lie in the fact that the incidence of distress at the time of the event or psychological sequelae later did not differ between cases reported early and late 29. Also, in studies using the Brice interview, a low proportion (about one third) of patients report pain or distress associated with their AAGA experience (i.e. the majority appear to make a neutral report) 7, 8, 31. This is similar to the proportion reporting distress in the NAP5 baseline survey 2, but somewhat lower than the 50% we have reported 29. Of relevance, Villafranca et al. described a patient who responded positively to a Brice interview, but maintained that the experience was so trivial that he did not wish to discuss it further 32.

Yet, in some support of the second interpretation, a number of the statement‐only cases in NAP5 clearly exhibited forms of phobic avoidance for decades after AAGA 4 (see also Chapter 25 of full report: http://www.nationalauditprojects.org.uk/NAP5Doc_NAP5_Baseline_Survey_in_the_UK). The relative proportion of relatively trivial vs relatively traumatic experiences in a Brice‐positive cohort is unknown and warrants formal investigation.

Induction of anaesthesia and transfer to theatre Accidental awareness around the time of induction of anaesthesia is not widely discussed in the literature. A previous review has suggested that three quarters of cases of AAGA occur during surgery itself 33, 34. A novel finding of NAP5 is that the period from the start of induction of anaesthesia to the start of the surgical intervention, including induction of anaesthesia and transfer into theatre, is the time when AAGA most commonly occurred. About half these reports involved cases categorised as urgent or emergency, and many of these involved rapid sequence induction, usually with thiopental. There were many cases where no opioid was used at induction of anaesthesia, particularly when conducted by a trainee, and failing to continue anaesthesia during difficult airway management attempts was judged contributory to AAGA in a number of cases. These results suggest that more careful attention to dosing of induction agent is needed, along with a proper assessment that it has worked sufficiently well before neuromuscular blocking drugs are administered. In turn, this finding requires a fundamental reassessment of what is intended by rapid sequence induction of anaesthesia, or even how it is defined, since this was such a potent risk. Rapid sequence induction accounted for most occasions when thiopental was administered, and this combination appeared to be an important risk factor for AAGA. Relevant questions include: whether co‐administration of opioids or other adjuncts lowers the risk of AAGA while still achieving the goals of rapid sequence induction; whether there is time to assess the effect of the induction agent and provide more if needed; whether the administration of the rapidly acting neuromuscular blocking drug can be delayed slightly to check the conscious level, and/or even check the ease of bag‐mask ventilation 35-38, itself a test of depth of anaesthesia; and whether thiopental should continue to have a place. The high proportion of AAGA cases associated with failed, prolonged or difficult airway management indicates an overlap between the findings of NAP4 39 and NAP5. Safe airway management should go hand‐in‐hand with appropriate delivery of anaesthetic to maintain unconsciousness. Importantly, the gap between intravenous induction and commencement of inhalational anaesthesia, often associated with transfer of the patient from anaesthetic room to theatre, was identified as a major factor in many AAGA cases. We therefore propose that a formal checklist, to be integrated as an anaesthetic sub‐component of the WHO checklist, is trialled (Fig. 4). Figure 4 Open in figure viewer PowerPoint A proposed NAP5 anaesthesia component (AC) checklist of the World Health Organization checklist (NAP5 AC‐WHO). The ABCDE check should be undertaken before commencing surgery (at the WHO surgical pause) and after each occasion the patient is moved.

Maintenance of anaesthesia Previous studies of AAGA have focused on events during the maintenance phase of anaesthesia – during surgery itself. Ghoneim et al. suggested that 75% of episodes of AAGA occurred during the maintenance phase 27, 33. However, only a third of NAP5 cases fell into this category, and this is consistent with our baseline survey 2. Many of these were in fact due to contributory factors at or after induction of anaesthesia, such as failure to turn on the vaporiser after transfer into theatre. Other contributory factors identified were deficiencies in end‐tidal monitoring or in responding to monitored levels of end‐tidal volatile agent, stopping delivery of the volatile agent too soon before the end of surgery, and using intentionally low doses. An important finding in cases of AAGA during surgery was that pain was more often a feature of the patient's experience than during other phases. Another important finding was that in 13 (26%) cases of AAGA during maintenance, no cause could be found, perhaps consistent with an innate resistance to the anaesthetic.

Emergence from anaesthesia An important finding of NAP5 is that residual neuromuscular blockade during tracheal extubation or emergence from anaesthesia may be interpreted by patients as AAGA. Almost one‐fifth of the reports to NAP5 occurred during emergence, most of which described experiencing the distress of paralysis 29. Failure to use a nerve stimulator was judged causal or contributory in the majority of the reports. These cases highlight the fact that adverse outcomes were more often associated with the use of neuromuscular blocking drugs. Overall, AAGA was associated with use of neuromuscular blocking drugs, failure to monitor their effects, and failure to reverse residual drug. These findings have at least two very important implications. The first relates to our view of neuromuscular monitoring. Based on our results, we propose that a nerve stimulator should be regarded as a monitor of motor capacity. The train‐of‐four, or another suitable index, signifies obtunded motor capacity, which leads to distress if the patient is conscious. A full return of neuromuscular function as assessed by nerve stimulation is a necessary but not sufficient condition for motor capacity. A patient in whom motor capacity has only just returned may still feel partially paralysed, and lack full muscle strength, and therefore can become distressed. Good understanding of this notion of motor capacity is fundamental to understanding the proper role of the nerve stimulator in anaesthetic practice. A second implication is for the planning of awake tracheal extubation. Patients should be informed in advance if there is a possibility or indeed if it is likely that they may wake up with a tube in their throat, and perhaps a temporary sensation of weakness or inability to move, or assisted breathing. In addition, full recovery from NMB should be confirmed both objectively using a nerve stimulator and clinically. During this period, continuous communication with the patient and verbal reassurance may mitigate any adverse recall of events 40.

Neuromuscular blockade Neuromuscular blockade was greatly over‐represented in the AAGA cohort compared with the activity survey, while the use of nerve stimulators and reversal agents were both under‐represented (Fig. 3). The cases of AAGA reported to NAP5 were perhaps more accurately, and overwhelmingly, cases of unintended awareness during neuromuscular blockade (Table 1), a term that could, or should, be a subtitle to this NAP5 report. The high incidence of distress in this cohort is examined in the accompanying paper 29 and it is clear that the sensation of paralysis has the capacity to cause great psychological harm, unless it is counteracted by general anaesthesia. Reflecting on these reports of AAGA, it can be argued that one of the main purposes of general anaesthesia is to enable patients to tolerate the global paralysis required for some surgeries. More than pain, it would seem uncommon for conscious patients to tolerate complete paralysis. Important ways to reduce AAGA might therefore include avoiding or minimising the use of neuromuscular blocking drugs and always using a nerve stimulator before allowing emergence from anaesthesia.

Syringe swaps and drug error We have reported 17 cases of brief awake neuromuscular blockade as a result of drug errors that led to administration of a neuromuscular blocking drug to a patient who was not anaesthetised. Importantly, distress and longer‐term psychological impact was of greater severity than in any other class of AAGA 29. There were numerous contributory factors: staff shortages; pressured environment; hospital policies for the storage and preparation of drugs; and distractions, commonly from other staff. Shortcomings in individual conduct involved a lack of vigilance and undue haste. A sustainable solution may require industry to work with the specialty with respect to drug packaging and presentation, in order that the risk of drug misidentification may be minimised. Institutions and individual anaesthetists need to develop organisational and personal strategies, respectively, to avoid circumstances that increase the likelihood of error, especially where neuromuscular blocking drugs are involved. Where a drug error leading to accidental paralysis has occurred there are three priorities: reassuring the patient that he/she is safe; induction of anaesthesia promptly to mitigate any continued adverse impact; and consideration of reversing neuromuscular blockade at an appropriate time guided by nerve stimulator monitoring.

Specific depth of anaesthesia monitoring Depth of anaesthesia monitors feature little in our results. This may be because such monitors are very rarely used in the UK. The activity survey estimated that just 2.8% of all general anaesthetics involve the use of any form of depth of anaesthesia monitoring 5. This is despite guidance from the National Institute for Health and Care Excellence 41, a full year before the activity survey was conducted, notwithstanding some criticism 42. The isolated forearm technique is even less frequently employed, despite prominent debate in the literature 43-46. The use of depth of anaesthesia monitors in Ireland is somewhat higher, 9% of all general anaesthetics 18, 19, but it is unknown if this pattern is mirrored in other countries. There was an over‐representation of the use of a depth of anaesthesia monitor in AAGA cases by 50%, superficially suggesting a lack of benefit. However, we do not know if they were used appropriately. Furthermore, these monitors appeared to be used selectively 2, 19. In the activity survey, these monitors were used in 1% of cases using volatile anaesthesia without neuromuscular blockade, but in 23% of cases using total intravenous anaesthesia with neuromuscular blockade (Table 4). Of all the anaesthetic techniques, total intravenous anaesthesia with neuromuscular blockade appears to confer the greatest (almost fourfold) risk of AAGA (Table 4). Furthermore, the data suggested a potential benefit of using depth of anaesthesia monitors with this last technique, but not especially for other anaesthetic techniques (Table 5). This crude analysis, however, does not take into account obesity, sex, or age as potentially influencing the selection of anaesthesia technique or monitoring. One implication of Tables 3 and 4 is that focusing on specific subgroups, such as total intravenous anaesthesia with neuromuscular blockade, might yield the most unambiguous results in clinical trials of monitor efficacy. Table 4. Risk profile of different anaesthetic techniques for AAGA. Proportions of anaesthetic technique as used in the activity survey (n, annual estimates, rounded up to nearest 100), compared with their representation in our cohort of certain/probable and possible AAGA cases. In the last column, a ratio of > 1 indicates over‐representation in the AAGA cohort; < 1 indicates under‐representation. Values are number (proportion). Activity survey (n = 2 667 000) Cases of AAGA with NMB specified (n = 118) Ratio of AAGA % to activity survey % Volatile, no NBD 1 357 600 (51%) 7 (6%) 0.12 Volatile, NBD 1 095 100 (41%) 90 (76%) 1.86 TIVA, no NBD 95 200 (4%) 3 (2%) 0.68 TIVA, NBD 108 400 (4%) 18 (15%) 3.73 Table 5. Use of processed EEG monitoring in different types of general anaesthesia in the activity survey (n, annual estimates) and in the certain/probable and possible cases of AAGA. In the last column, a ratio of < 1 indicates use of the monitor may have a protective effect against AAGA, such that there is under‐representation in the AAGA cohort; > 1 indicates the reverse. Values are number (proportion). EEG monitoring in activity survey EEG monitoring in AAGA cases Ratio All general anaesthetics (n = 2 667 600) 73 600 (3%) 6 (5%) 1.82 Volatile agent, no NBD (n = 1 357 600) 15 000 (1%) 0 –* Volatile agent, NBD (n = 1 095 100) 38 300 (4%) 3 (3%) 0.94 TIVA, no NBD (n = 95 200) 7400 (8%) 1 (33%) 4.27 TIVA, NBD (n = 108 400) 25 400 (23%) 2 (11%) 0.47

Total intravenous anaesthesia Total intravenous anaesthesia, which included target‐controlled, manually controlled infusion and fixed‐rate infusions as well as bolus techniques, were over‐represented compared with the activity survey. Failure to deliver the intended dose of drug, for example because of a problem with the intravenous cannula, resulted in a number of cases of AAGA. However, the greatest over‐representation was for instances where a volatile technique was converted to TIVA for transfer of patients out of theatre (Table 6). Many of these cases occurred outside theatres and in circumstances where a volatile anaesthetic could not be delivered. In summary, the commonest cause was the administration of an inappropriately low‐dose, fixed‐rate infusion of propofol to patients in whom neuromuscular blocking drugs had been used. Table 6. Techniques used to maintain anaesthesia where general anaesthesia was induced in an operating theatre or theatre anaesthetic room, and certain/probable and possible AAGA reported (totals in the activity survey reporting period and AAGA cases). In the last column, a ratio of > 1 indicates over‐representation in the AAGA cohort; < 1 indicates under‐representation. The totals (n) are for the activity survey reporting period and AAGA cases. Total; n (%) AAGA; n (%) Ratio Volatile agent 13 479 (93%) 112 (82%) 0.89 Propofol infusion TCI* 764 (5%) 14 (10%) 1.94 Propofol infusion not TCI 82 (0.6%) 2 (1.5%) 2.50 Intermittent boluses* 106 (0.7%) 1 (0.7%) 1.00 Both volatile agent and propofol infusion 48 (0.3%) 7 (5%) 17.00 Total 14 479 136 –

Obstetric anaesthesia We have confirmed that obstetric anaesthesia is a high risk for AAGA – it was the most markedly over‐represented of all surgical specialties. The vast majority of obstetric cases occurred during caesarean section. There was also an impression that general anaesthesia for caesarean section involved many of the risk factors for AAGA identified elsewhere in NAP5. These included: rapid sequence induction of anaesthesia, omission of opioids at induction, almost always using thiopental and sometimes at inappropriately low doses; universal use of neuromuscular blocking drugs; difficult airway management; obesity; brief period between anaesthetic induction and start of surgery with little time for reinforcement of the intravenous induction dose with a volatile agent; and a high incidence of urgent/immediate surgery often performed out of hours, resulting in higher rates of non‐consultant care.

Cardiothoracic anaesthesia and AAGA in cases from ICU We have confirmed that cardiac anaesthesia is also a high risk for AAGA. Most of the reports involved either brief interruption of drug delivery, caused by human error or technical problems, or the use of intentionally low doses of anaesthetic drugs in high‐risk patients, such as those with cardiovascular instability. There were seven reports of cases of AAGA during anaesthetic interventions on ICU. There appeared to be underestimation of anaesthetic requirements in sick, hypotensive patients, usually using a low‐dose propofol infusion. All patients received neuromuscular blocking drugs and experienced distress 29 and most episodes were judged to be avoidable.

Paediatric anaesthesia We identified AAGA to be much less common in children than in other series 14, at around 1:60 000. Some reports of AAGA were received by parents but not transmitted further, though the reasons for this are unclear. Others were first reported decades after the event, and by patients who reported significant psychological distress as a consequence. We classed patients aged up to 16 years old as children but just one case was reported by a patient aged < 5 years old. Differences in patient experience, memory formation, childhood perceptions and parental attitudes may have contributed. Also notable are a much reduced use of neuromuscular blocking drugs in children – 25% vs 50% in adults in the activity survey 5. However, when made, children's reports of AAGA appeared to be as reliable as adults', and we emphasise that children should be believed and treated sympathetically.

Inherent resistance to anaesthetic agents There was some evidence from our data of differential risk of AAGA with different anaesthetic agents (Fig. 3): increased risk with thiopental and reduced risk with sevoflurane compared with other volatile agents. Variation in the risk of AAGA with different anaesthetic agents and the potential for heterogeneity in coding for protein channels on which anaesthetic agents are likely to act provide some support for the idea of a genetic role in patients' susceptibility to anaesthetic agents, or, conversely, risk of AAGA. Some support for this comes from NAP5's finding that, in 25% of AAGA reports arising in the maintenance phase of anaesthesia, the cause was unexplained. Also, six patients of our cohort had previously experienced AAGA, and one appeared to have a family history of AAGA, suggesting that 5% of reports may have an intrinsic basis.