Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment

Population

Human patients of any age and health status, undergoing in-hospital surgery involving general anaesthesia and requiring NMB.

Intervention and comparators

The intervention and comparators were different for routine and rapid intubation.

Routine intubation In routine intubation the intervention is sugammadex 2 or 4 mg/kg for reversal of moderate or profound NMB, respectively, induced by rocuronium or vecuronium.

For routine intubation, trials comparing any of the following NMBAs + reversal agent combinations were eligible for inclusion:

• rocuronium or vecuronium + sugammadex

• rocuronium, vecuronium, atracurium, cisatracurium or mivacurium + neostigmine–glycopyrrolate

• rocuronium, vecuronium, atracurium, cisatracurium or mivacurium + no reversal (i.e. spontaneous recovery) or placebo.

To be eligible, sugammadex studies were required to compare rocuronium or vecuronium + sugammadex with each other, with any listed NMBA + neostigmine and glycopyrrolate or with any listed NMBA + no reversal agent (placebo or spontaneous recovery). Comparisons not involving sugammadex were included to develop a network of evidence related to the reversal of moderate NMB in elective surgery. To be eligible, studies had to administer a reversal agent (neostigmine or placebo) at the return of T2 (second twitch of the TOF – the point at which sugammadex was given in studies of moderate block) or at an alternative point (T1 20% or 25%) based on TOF monitoring and considered to represent an equivalent degree of recovery. Studies in which no placebo was given in the ‘no-reversal-agent’ arm (i.e. spontaneous recovery) were included, provided that TOF outcomes were measured from one of the appropriate time points.

Rapid intubation For rapid intubation and immediate reversal of NMB, trials of rocuronium + sugammadex compared with spontaneous recovery from succinylcholine-induced NMB, or with rocuronium + placebo, were eligible for the review.

Outcomes

Studies reporting the following outcomes were eligible for the review: speed of reversal of NMB as measured by TOF monitoring (e.g. recovery of the T4/T1 ratio, i.e. ratio of the height of the fourth twitch to that of the first, to 0.9) and clinical signs of recovery (e.g. able to perform the 5 s head-lift test21,22); occurrence of residual blockade; adverse event profile of intervention and comparators; and mortality, if reported. Studies reporting outcomes relating to the patient’s experience of recovery and any outcomes relating to improved control of anaesthesia or resource use were also included.

The primary outcome used in the review was time from administration of a reversal agent to recovery of the T4/T1 ratio to 0.9 (90% of baseline value); secondary outcomes based on TOF monitoring included recovery of the TOF ratio to 0.7 and 0.8 and, for comparing sugammadex with succinylcholine, recovery of T1 (first twitch of the TOF) to 0.1 and 0.9 in rapid intubation and immediate reversal of NMB.

Study designs

For the assessment of the clinical efficacy of sugammadex, only parallel-group RCTs were included.

Exclusion criteria

Animal models, preclinical and biological studies, case reports, studies of healthy volunteers, reviews, editorials and opinions were excluded.

Sugammadex

In addition to studies included in the main clinical effectiveness review, safety data included in manufacturer submissions to regulatory authorities and in reports by regulatory authorities were eligible for the review. These included pooled analyses of safety data from studies that were not otherwise eligible for the review.

NMBAs, neostigmine and glycopyrrolate

We reviewed summary sources of data (see Chapter 3, Methods for reviewing clinical effectiveness, Search strategy) on these agents, with the objective of identifying the most important adverse effects and quantifying their incidence in surgical patients. Further database searches were performed to search for studies of any design reporting specific rates of adverse effects associated with NMBAs and the combination of neostigmine and glycopyrrolate. Preference was given to primary reports with a rate estimate based on a large sample with a known denominator.

Reversal of moderate block

Eleven studies were included in the assessment of sugammadex for reversal of moderate block: two active-control trials comparing sugammadex with N&G29,30 and nine placebo-controlled dose-finding and special population studies. Of these trials five have been published in full and six are available only as conference/poster abstracts, with supplementary information taken from the FDA and EMEA documents10,23 and details reported on the ClinicalTrials.gov website. One trial (19.4.208A)31 has not been published even in abstract form, but details were available in the Organon/Schering-Plough FDA submission. 23 Further details and quality assessment results for these trials are reported in the section Sugammadex for reversal of moderate NMB.

Reversal of profound block

A total of five studies (three active and two placebo-controlled trials) were included in the assessment of sugammadex for the reversal of profound NMB. Two of these studies have been published in full as journal articles,32–34 two are available only as short abstracts or publications reporting incomplete results35–38 and the final study has not yet been published. 39 In all cases, supplementary information was taken from the FDA and EMEA documents,10,23 and details reported on the ClinicalTrials.gov website. Further details and results of the quality assessment process are reported in the section Sugammadex for reversal of profound NMB.

Immediate reversal of NMB

Three trials (one active and two placebo-controlled trials) were included in the assessment of sugammadex for the immediate reversal of NMB. Full publications were available for two of the trials,34,40 but one41 was initially published only as an abstract, with additional data extracted from the EMEA and FDA documents. 10,23 Further details and quality assessment results are reported in the section Sugammadex for immediate/rapid reversal of NMB.

Study characteristics

Six studies were included in the assessment of sugammadex for reversal of moderate block. 16,29–31,49,50 The quality assessment results and characteristics of the included studies are summarised in Tables 3 and 4. An additional five trials provided supplementary information on the use of sugammadex in special populations and are discussed in the section Other relevant evidence. 51–55 All 11 studies monitored NMB using acceleromyography (TOF-Watch^®). Many of the included trials were dose-finding studies, with the included patients distributed across many treatment dose arms, such that sample sizes per treatment arm were very small. Total sample sizes for relevant treatment arms (i.e. sugammadex 2 mg/kg or placebo or comparator) ranged from 9 to 189 patients, with sample sizes per treatment group ranging from 1 to 48 patients.

Due to clinical and methodological differences among the active studies and special patient populations, meta-analyses across all studies were not appropriate, and data are therefore presented as a narrative synthesis. Furthermore, the results of the primary studies were reported variously using means and SDs, medians and ranges and geometric means and CI, indicating that much, if not all, of the data were likely to be skewed, making synthesis difficult.

Placebo-controlled trials

Four placebo-controlled studies were included in the review (n = 89): Sorgenfrei et al. ,16 Suy et al. ,49 an unpublished Japanese study 19.4.208A31 and Puhringer et al. 50 Quality assessment of these studies (Table 3) indicated that allocation concealment was not described, and, while most studies described themselves as randomised, none gave sufficient details to establish if true randomisation had been used (both abstracts and full papers). Power calculations were not always mentioned or described in any detail, but this is not surprising as many of the placebo-controlled trials were dose-finding studies and were not designed to assess efficacy. The treatment groups were usually judged to be comparable and exclusions/dropouts accounted for except where insufficient details had been reported. Major protocol violations were observed in two patients (one in each treatment arm) in Sorgenfrei et al. ,16 and monitoring data could not be obtained for one patient in the rocuronium + placebo group in Suy et al. ,49 thus these patients were excluded from the per-protocol analysis. Data on patient exclusions and violations were not available for the unpublished Japanese study31 or Puhringer et al. 50 In the first active-control study,30 two patients in the rocuronium group and seven patients in the vecuronium group did not receive treatment and were therefore not included in the intention-to-treat (ITT) analysis. Five patients in the rocuronium group and seven patients in the vecuronium group experienced major protocol violations and were therefore not included in the per-protocol population. In the second study,29 11 patients did not receive treatment and were therefore not included in the ITT analysis, and eight patients experienced major protocol violations and were therefore not included in the per-protocol group.

Study characteristics are reported in Table 4. Patients in all four studies received propofol as the induction anaesthesia, two also received this as the maintenance anaesthesia, while patients in the unpublished Japanese study23 and the Puhringer50 study received sevoflurane as the maintenance anaesthesia. All four trials were dose-finding studies, not designed as comparator efficacy trials. Patients received fentanyl, remifentanil, alfentanil or morphine as the analgesic agent. Two studies16,49 included patients undergoing surgery lasting at least 60 minutes and requiring muscle relaxation to facilitate tracheal intubation only, and one study included patients undergoing surgery in the supine position and lasting approximately 1.5–3 hours.

Suy et al. 49 and Sorgenfrei et al. 16 included patients belonging to ASA classes I and II, although there was a higher proportion of patients in ASA class I in Sorgenfrei,16 and the unpublished Japanese study23 included patients in ASA classes I–III. Comorbidity was not reported. Mean ages and mean weights differed slightly between Suy et al. 49 and Sorgenfrei et al. 16 (55 and 40 years, respectively, and 75 kg compared with 80 kg, respectively). Data were limited for the unpublished Japanese study31 and Puhringer et al. 50 and it was not possible to compare baseline characteristics for these studies (see Appendix 3).

Table 5 shows the time from administration of sugammadex or placebo, administered at reappearance of T2 following rocuronium or vecuronium, to recovery of the TOF ratio to 0.7, 0.8 or 0.9. There were clear differences in recovery times to TOF 0.9, with patients receiving sugammadex 2 mg/kg recovering faster than those receiving the comparators: median recovery times were 1.3–2.9 minutes with sugammadex, compared with 21.0–86.2 minutes with placebo. Furthermore, the recovery time was more predictable with rocuronium + sugammadex: recovery to TOF 0.9 was 0.7–4.8 minutes compared with 15.0–153.0 minutes with rocuronium and placebo. Similar findings were seen with vecuronium: vecuronium + sugammadex recovery to TOF 0.9 was 1.3–7.1 minutes compared with 27.1–141.1 minutes with vecuronium and placebo.

Outcomes for mortality, patient experience/QoL, and costs and resources were not reported.

Active-control trials

Results of the quality assessment process are reported in Table 3. The two active-control studies29,30 largely conformed to the expected quality criteria bearing in mind the lack of blinded primary outcome assessment, and it was unclear if the safety assessments were performed blind to treatment allocation in the study of Blobner et al.

The details of the two active-control trials29,30 are summarised in Table 4. One study30 compared rocuronium + sugammadex with rocuronium + neostigmine–glycopyrrolate, and also compared vecuronium + sugammadex with vecuronium + neostigmine–glycopyrrolate. The other active-control trial compared rocuronium + sugammadex with cisatracurium + neostigmine–glycopyrrolate. 29 The two active trials largely conformed to the expected quality criteria (Table 3) except that it was unclear if the safety assessments were performed blind to treatment allocation in the study of Blobner et al. 30

Baseline characteristics were similar in both studies in terms of ASA Physical Status, with all patients classed as ASA I, II or III. Comorbidity was not reported. Both studies included patients undergoing surgery in the supine position and all patients received propofol as the induction anaesthesia. Patients in the comparison with neostigmine30 received sevoflurane as the maintenance anaesthesia, while patients in the comparison with cisatracurium and neostigmine29 continued with propofol and also received an analgesic (remifentanil, fentanyl or sufentanil). The use of nitrous oxide was not reported in either study (see Appendix 3 for further details).

Table 6 shows the time from administration of sugammadex or neostigmine, administered at reappearance of T2 following rocuronium, vecuronium or cisatracurium to recovery of the TOF ratio to 0.9, based on ITT analysis. Statistical analysis conducted by the primary study authors29,30 (two-way analysis of variance) indicated significantly faster recovery times after rocuronium + sugammadex (median 1.4 minutes) compared with rocuronium + neostigmine (median 17.6 minutes), and faster recovery times in patients receiving vecuronium + sugammadex (median 2.1 minutes) compared with patients receiving vecuronium + neostigmine (median 18.9 minutes). 30 A significant difference in recovery times was also reported between rocuronium + sugammadex (median 1.9 minutes) versus cisatracurium + neostigmine (median 7.3 minutes). 29 Furthermore, the recovery time was more predictable with rocuronium + sugammadex: recovery to TOF 0.9 was 0.9–5.4 minutes in one trial and 0.7–6.4 minutes in the other, compared with 3.7–106.9 minutes with rocuronium and neostigmine, and 4.2–28.2 minutes with cisatracurium and neostigmine.

Similar trends were also observed for recovery times to TOF 0.8 and 0.7 (Table 6), with median recovery times in the rocuronium + sugammadex group faster for both outcomes (1.5 and 1.2 minutes, respectively) compared with the cisatracurium + neostigmine group (5.9 and 4.7 minutes, respectively) both p < 0.00001 (primary authors’ analysis). 29

Clinical signs of recovery were reported in Flockton et al. ,29 with 22 out of 34 patients (65%) in the sugammadex group and 27 out of 39 patients (69%) in the neostigmine group awake and orientated before transfer to the recovery room. The majority of patients in both treatment groups were reported to be cooperative, able to perform a 5-second head-lift, and did not experience muscle weakness before transfer to or before discharge from the recovery room.

Summary of sugammadex for reversal of moderate block

Data from trials of sugammadex for the reversal of moderate block were reported variously as arithmetic mean, geometric mean and median + range. Based on small numbers of patients, the median time from administration of sugammadex 2 mg/kg at return of T2 to recovery of TOF 0.9 appears to be approximately 2 minutes (medians varied from 1.3 to 2.9 minutes). Placebo-controlled dose-finding studies indicate that recovery of the TOF ratio is significantly faster with sugammadex than placebo, although the magnitude of the difference varied between studies. Two active-control studies indicate significantly faster recovery times using sugammadex versus neostigmine after NMB induced with rocuronium, vecuronium or cisatracurium. 29,30 Furthermore, the recovery time was more predictable with sugammadex than with placebo or other reversal agent, as shown by much smaller ranges reported in all trials.

Validity assessment of non-sugammadex studies

As shown in Table 8, only one study met all of the quality assessment criteria;44 however, the sample size was still relatively small. Methods of randomisation were not always reported, and the use of allocation concealment was difficult to establish for most studies. Outcome assessors were not always reported as being blinded but three trials appear to have used full blinding. Overall, the treatment groups were usually judged as being comparable, and all withdrawals and exclusions were accounted for. These studies all used small samples with multiple treatment arms and only three reported power calculations informing the sample size decisions. Despite being published within the last 10 years, overall the reporting was poor, making it difficult to judge the quality of the research.

Results of non-sugammadex studies

The results of the various comparisons made in these seven trials are summarised in Table 9. Neostigmine significantly decreased time to recovery of the TOF ratio 0.8 or 0.9 compared with placebo or spontaneous recovery after administration of both rocuronium and cisatracurium (p < 0.05 based on primary authors’ analysis). 42,44 Bailey and Nicholas43 reported significantly faster recovery times to TOF 0.7 following vecuronium + neostigmine (mean 2.57 minutes) compared with atracurium + neostigmine (mean 4.26 minutes) (p < 0.001 based on primary authors’ analysis). By comparison, Della Rocca et al. 48 showed faster times to recovery of the TOF ratio to 0.8 following administration of atracurium or cisatracurium + neostigmine compared with rocuronium or vecuronium + neostigmine, and Berg et al. 45 reported similar recovery times to TOF 0.8 for all patients following administration of vecuronium + neostigmine and atracurium + neostigmine [median 25 (6–52) and 23 (7–52) minutes, respectively].

Other trials indicate that recovery rates are similar with rocuronium + neostigmine and vecuronium + neostigmine,46 and between cisatracurium + neostigmine and atracurium + neostigmine. 47

Overall, these trials demonstrate that neostigmine is effective at shortening time to recovery from T2, or its equivalent (T1 20% or 25%), to TOF ratio 0.7, 0.8 or 0.9 after administration of rocuronium or cisatracurium.

Mixed-treatment comparison

The purpose of the MTC was to bring together the clinical evidence regarding the routine reversal of shallow/moderate block. In order to conduct a MTC, treatments need to be linked into a chain or network of evidence. In this instance those treatments that could be linked (i.e. those with time of recovery measured as time from T2 or equivalent to TOF 0.9) included rocuronium + sugammadex (2 mg/kg), rocuronium + placebo, vecuronium + sugammadex (2 mg/kg), vecuronium + placebo, rocuronium + neostigmine, vecuronium + neostigmine, cisatracurium + neostigmine and cisatracurium + placebo. Summary statistics showing mean or median time to TOF 0.9 were identified. In addition, a number of trials reported TOF 0.7 or 0.8, which it was hoped would allow us with the use of econometric techniques to estimate a TOF 0.9. This would also have allowed an additional comparator, atracurium + neostigmine, to be incorporated into the network. However, in order to estimate TOF 0.9 using the TOF 0.7 and 0.8 data, it would have been necessary to assume that the relationship between the TOF ratios was the same across all comparators. After some discussion it was felt that this was unreasonable and all studies reporting TOF 0.7 and 0.8 were excluded from the network.

However, despite the exclusion of these studies, there were still a number of problems identified with the remaining data. Firstly, it was unclear whether the mean data reported for TOF 0.9 were appropriate. Given the small sample sizes and unequal variances it is possible that the data were in fact skewed data, rather than normally distributed. Also, where medians were reported it was necessary to have or to calculate the 95% CIs of those summary estimates, in order to undertake the analysis. Unfortunately, this was not possible from the published data available to us and we were unable to obtain data from the manufacturer of sugammadex, Schering-Plough, despite repeated requests. In order to estimate the 95% CIs we would have needed to make some assumption about the likely distribution of the data, and while such an assumption was possible, it was not possible without further data to validate any such distributional assumption. If a false distributional assumption was made, the results generated could be spurious and any inferences made on the basis of these calculations would need to be made in a highly conservative fashion. Therefore, it was concluded that the MTC analysis could not be undertaken at this time. Further research into the possibility and implications of using different statistical methods to achieve the MTC could be investigated, but this would be outside of the resources and scope of this project.

Narrative synthesis

The available trial data indicate that in patients without comorbid disease, recovery to a TOF ratio of 0.9 is substantially faster when NMB is reversed with sugammadex following rocuronium or vecuronium (mean recovery times ranged between 1.4 and 2.2 minutes, and between 2.3 and 3.4 minutes, respectively) compared with reversal with neostigmine after rocuronium (between 4.5 and 10 minutes) or vecuronium (mean 6.0 minutes) and spontaneous recovery after rocuronium (43.1 and 56.7 minutes). Similar trends were observed in studies of cisatracurium, with recovery times to TOF 0.9 of 11.5 and 11.7 minutes following reversal with neostigmine, and 49.2 and 52.5 minutes for spontaneous recovery.

Overall, the non-sugammadex trials demonstrate that neostigmine is effective at shortening time to recovery (from T2 or an equivalent time point to TOF 0.7, 0.8 or 0.9) with all NMBAs studied, including rocuronium, vecuronium, cisatracurium and atracurium. The evaluation of the evidence for sugammadex demonstrated that the combination of rocuronium + sugammadex and vecuronium + sugammadex resulted in a substantially shorter time to recovery than did rocuronium + neostigmine and vecuronium + neostigmine. In addition, rocuronium + sugammadex resulted in a statistically significantly shorter time to recovery compared with cisatracurium + neostigmine. 29 Therefore, the data would suggest that use of rocuronium or vecuronium + sugammadex would result in shorter recovery times than the use of these NMBAs with neostigmine, and use of sugammadex with rocuronium or vecuronium may be shorter than cisatracurium/atracurium neostigmine combinations. However, these tentative conclusions are limited by the lack of a more formal and explicit analysis.

Placebo-controlled trials (reversed at 15 minutes)

Both placebo-controlled trials on profound block32,34 evaluated reversal after 15 minutes of 0.6-mg/kg rocuronium block with sugammadex (4 mg/kg). Both trials assessed the dose–response relationship and efficacy of five doses of sugammadex or placebo for the reversal of profound rocuronium block (0.6-mg/kg intubating dose32 and 1.0-mg/kg or 1.2-mg/kg intubating dose34). The results for times to recovery of TOF 0.7, 0.8 and 0.9 are presented in Table 12. Results of one trial32 were reported based on the per-protocol population, as the ITT population included one patient assigned to sugammadex who received placebo and this was deemed to inappropriately influence the dose–response curve. The results of the second trial were reported for the ITT population. For the primary outcome of time to TOF 0.9, recovery with 4-mg/kg sugammadex was clearly faster than the placebo group for all three doses of rocuronium investigated (medians of 1.5–5.6 minutes versus 30.6–94.2 minutes).

Both of these small placebo-controlled dose-finding studies appear to be of high internal validity, although neither was designed as an efficacy trial, and provide some support to the hypothesis that sugammadex can reverse profound NMB.

Active-control trials (reversed at PTC 1–2)

Two of these studies35,39 were randomised dose-finding rather than efficacy studies, of which only the arms using 4 mg/kg of sugammadex for reversal are of interest and discussed in this section. Two arms within these studies used 4 mg/kg of sugammadex for reversal at PTC 1–2; one arm used 0.9 mg/kg of rocuronium, and the other used vecuronium 0.1 mg/kg. The results (Table 12) are based only on per-protocol summaries, which excluded data from any major protocol violations. Median time to recovery of TOF 0.9 was 1.2 minutes and 1.5 minutes in the rocuronium arms, while in the vecuronium arms median recovery time was 1.9 minutes and 2.3 minutes, suggesting that recovery from NMB may be faster when induced by rocuronium than with vecuronium.

The key comparative study for this indication36–38 was a multicentre trial that compared sugammadex and neostigmine in the reversal of profound vecuronium- or rocuronium-induced blockade. Table 12 shows the study results for time to recovery of TOF 0.9 after reversal of profound block at PTC 1–2 with sugammadex or neostigmine. Statistical analysis by the study authors, using two-way analysis of variance on log-transformed recovery times, indicated that there was a significant difference between sugammadex and neostigmine in both the rocuronium and vecuronium groups (p < 0.001). Within the rocuronium group, median recovery time after reversal with sugammadex was 2.7 minutes compared with 49.0 minutes with neostigmine. In the vecuronium group, reversal time with sugammadex was 3.3 minutes compared with 49.9 minutes with neostigmine; however, there was a greater interindividual variation in recovery times for vecuronium + sugammadex than for rocuronium + sugammadex.

In summary, this trial provides randomised evidence that sugammadex can effectively reverse profound NMB (vecuronium or rocuronium induced) when the patient has recovered to PTC 1–2, a situation where there is currently no other alternative reversal agent available.

Summary of sugammadex for reversal of profound blockade

The ability to reverse profound NMB using sugammadex 4 mg/kg, administered at PTC 1–2 or an equivalent time point, is potentially an important benefit of sugammadex, as existing reversal agents are not able to reverse this level of blockade. Placebo-controlled dose-finding studies (based on reversal 15 minutes after administration of the NMBA) indicate a substantially faster recovery with sugammadex than placebo, although the magnitude of the effect varies. A single trial36–38 found significantly faster recovery times to TOF 0.9 for sugammadex compared with neostigmine–glycopyrrolate for both rocuronium- and vecuronium-induced blockade (medians of 2.7 versus 49.0 minutes for rocuronium and 3.3 versus 49.9 minutes for vecuronium).

Study characteristics

Characteristics of the three studies are summarised in Table 14. Patients were almost all in ASA classes I and II, although one trial34 had a higher proportion of ASA II patients than the others. About one-half of the patients were male. Patients in the placebo-controlled trials were undergoing surgery lasting 90 minutes or more, while those in the active-control trial required only a short duration of muscle relaxation. No trial reported comorbidity. All the trials used propofol for induction and maintenance of anaesthesia.

The two placebo-controlled trials were dose-finding studies. 34,40 The main active-controlled trial compared sugammadex for reversal of rocuronium-induced block with spontaneous recovery from NMB induced by succinylcholine. This study was not fully published at the time of writing and data were extracted from the abstract by Lee et al. 41 and various other publications (see Appendix 3).

Placebo-controlled studies

Two randomised safety assessor-blinded placebo-controlled trials assessed recovery from rocuronium-induced NMB in patients treated with sugammadex (16 mg/kg) or placebo. In one trial, sugammadex or placebo was administered 5 minutes after an intubating dose (1.2 mg/kg) of rocuronium. 40 In the second trial, sugammadex or placebo was administered 3 minutes after an intubating dose (1.0 or 1.2 mg/kg) of rocuronium. 34 Both trials were designed to explore dose–response relationships and had small numbers of patients in the 16-mg/kg and placebo arms (Table 14). Randomised patients who received treatment and had at least one postbaseline efficacy assessment without any major protocol violations were included in the efficacy analyses. The results of the two trials (Table 15) were similar to one another and support the hypothesis that sugammadex provides a rapid reversal of NMB induced by high doses of rocuronium when administered shortly after the NMBA. The differences in time to recovery of the TOF ratio between patients treated with placebo and 16-mg/kg sugammadex were large. The results are summarised in Table 15.

Active-control study: rocuronium + sugammadex versus succinylcholine

One multicentre RCT involved adult patients aged 18–65 years, and belonging to ASA class I or II, who were undergoing elective surgery requiring a short duration of NMB. Patients were randomised to receive an intubating dose of rocuronium (1.2 mg/kg), followed by sugammadex (16 mg/kg), 3 minutes after the start of rocuronium administration or an intubating dose of succinylcholine (1 mg/kg), followed by spontaneous recovery. NMB was monitored by acceleromyography using the TOF-Watch^®. Unlike all other sugammadex trials, the primary efficacy end point was time to recovery of T1 (first twitch of the TOF) to 10% of the control value. This end point was chosen as a surrogate for the appearance of signs of clinical recovery, such as diaphragm movement and return of ventilation on the capnogram, which were expected to occur 4.5 minutes or more after administration of succinylcholine. 23

A total of 115 patients were randomised in this study, 57 to rocuronium + sugammadex and 58 to succinylcholine; 56 and 54 patients, respectively, received treatment and the ITT population for which results were reported contained 55 patients in each group. There were no major differences between groups in baseline characteristics (see Appendix 3). However, 18 patients in the sugammadex group received medication expected to enhance the effects of NMBAs (primarily inhalational anaesthetics) compared with 11 in the succinylcholine group. 12 This was classed as a major protocol violation and could have biased the study results against sugammadex.

Table 16 shows the study results for time from administration of rocuronium or succinylcholine to T1 of 10% and 90%. The study authors’ analysis by two-way analysis of variance indicated that the difference between groups was significant (p < 0.001) for both outcomes. The time from the start of administration of sugammadex to recovery of the TOF ratio to 0.9 was measured in the rocuronium + sugammadex group (Table 16). 58 This ancillary analysis also showed that most patients (87%) had recovered to a TOF ratio of 0.9 by 3 minutes after administration of sugammadex. 58 Times to TOF ratios of 0.7 and 0.8 (assumed to be means) were 1.3 and 1.5 minutes, respectively.

Clinical signs of recovery did not show any differences between groups. 58

In summary, this study provides randomised evidence that recovery of T1 to 10% and 90% of control values is significantly faster following blockade induced by rocuronium and reversed by sugammadex 16 mg/kg compared with blockade induced by succinylcholine followed by spontaneous recovery. However, there was a degree of overlap in the range of recovery times between the two groups, and it would be interesting to have more data on the distribution of recovery times.

None of the studies involving rapid reversal of blockade reported on outcomes related to QoL, costs or resource use, although a Quality of Recovery questionnaire was used in the active-control study. 12 Safety outcomes were assessed and the results included in the summary documents discussed in Other relevant evidence.

Summary of sugammadex for immediate/rapid reversal

The ability to rapidly reverse rocuronium-induced NMB using 16-mg/kg sugammadex could be a valuable tool for the clinician in a situation of rapid sequence induction of anaesthesia or if a ‘cannot intubate–cannot ventilate’ emergency arises. The three studies included in this section indicate that the end point of TOF ratio 0.9 can be reached rapidly in most patients.

Renal patients

This study51 compared the response to sugammadex in patients with and without renal impairment. Thirty patients were included in the study; 15 with renal impairment (CR_CL < 30 ml/minute) and 15 healthy control patients (CR_CL > 80 ml/minute). The majority of patients with renal failure belonged to ASA class III (93%), compared with control patients who belonged to ASA class I or II. 10 The results for one control patient were unreliable and were therefore excluded from the analysis.

Baseline characteristics were comparable for both groups in terms of age, weight, height, gender and ethnicity. There was a substantial difference in mean CR_CL for patients with renal impairment (12 ml/minute) compared with healthy control patients (103 ml/minute). Ten renal patients with end-stage renal failure were receiving dialysis.

Recovery times were slightly slower in renally impaired patients compared with control patients, but this was not significantly different (p = 0.06), and NMB was effectively reversed in both patient groups. Similar results were reported for time to recovery of TOF 0.7 and 0.8, with no significant differences between the two patient groups (Table 19).

Elderly patients

Time to recovery of TOF 0.9 following administration of rocuronium and sugammadex, was reported as 2.3 minutes (geometric mean) in adult patients (≤ 65 years) compared with elderly (65–74 years) and old-elderly patients (≥ 75 years) (geometric means of 2.6 and 3.6 minutes, respectively). 55 This difference was statistically significant (p = 0.022, based on primary authors’ analysis), but may not be clinically relevant.

Children

Patients were scheduled for general surgery requiring at least 60 minutes of anaesthesia. 52 Table 20 shows the time from administration of sugammadex or placebo administered at reappearance of T2 following rocuronium, to recovery of the TOF ratio to 0.9.

The difference in mean recovery times indicate that recovery to TOF 0.9 with sugammadex is substantially faster than recovery times after placebo across all ages investigated. Recovery times in adults may be slower than in adolescents, children and infants.

Pulmonary patients

This randomised placebo-controlled study53 compared recovery times in adult patients with a diagnosis or known history of pulmonary disease, such as asthma. 23 The geometric mean time to recovery of the TOF ratio to 0.9 was 2.1 minutes, similar to recovery times reported in the two active-controlled studies: 1.5 minutes30 and 1.9 minutes. 29

Cardiac patients

This multicentre, randomised, placebo-controlled study54 assessed the safety of sugammadex for the reversal of NMB induced by rocuronium in adult patients with cardiac disease (e.g. ischaemic heart disease, chronic heart failure or arrhythmia). 23 Patients belonged to ASA classes II, III or IV, but no further details were reported. Patients were undergoing elective, non-cardiac surgery in the supine position.

Time to recovery of the T4/T1 ratio to 0.9 was substantially faster in patients receiving sugammadex compared to patients in the placebo group (geometric mean 1.7 versus 34.4 minutes).

Summary of sugammadex special population studies

In special population studies, recovery times differed between the age groups, with infants showing the quickest recovery times. However, due to the low number of patients included, and the lack of statistical analysis, these findings should be interpreted with caution. Recovery times for reversal of rocuronium NMB using sugammadex were comparable for patients at increased risk of pulmonary disease and patients without pulmonary complications, and for patients with and without cardiac or renal disease.

Residual blockade/recurrence of blockade

Eight studies reported on residual blockade or recurrence of blockade. 45,62,63,65,69,71,72,78 The UK national survey by Light et al. 62 provided absolute numbers of events rather than specific rates. Three studies (two single-centre surveys63,65 and one RCT69) reported rates of residual blockade in the absence of reversal or with reversal agents not routinely used. The studies differed in their use of reversal agents, definition of residual blockade and the point at which blockade was evaluated (Table 23). In the study by Cammu et al. ,65 reversal agent use was not reported by drug but blockade was reversed in 25% of outpatients and 26% of inpatients. These three studies suggest that in the absence of reversal 25–50% of patients could have some degree of residual NMB (TOF ratio < 0.9) on arrival in the recovery room after treatment with a non-depolarising NMBA as part of their anaesthetic protocol. There were no obvious differences between the NMBAs that can be used with sugammadex (rocuronium and vecuronium) and those that cannot (atracurium, cisatracurium and mivacurium). Only Cammu et al. 65 reported on residual blockade following succinylcholine but the numbers involved were very small (overall 2/8, 25%).

Residual blockade despite the use of a reversal agent is more relevant to the assessment of sugammadex and data on incidence of this outcome were obtained from two RCTs45,71 and a systematic review78 (Table 24). The two RCTs reported rates of 5–6% of patients with residual blockade (TOF ratio < 0.7) following reversal of vecuronium, rocuronium or atracurium-induced block. The systematic review78 found no residual blockade following reversal of mivacurium or vecuronium-induced block in two trials (n = 90). These studies suggest that the risk of residual blockade following reversal with neostigmine–glycopyrrolate is at least in the range 0–6%, although if the more stringent criterion of a TOF ratio < 0.9 is used the rate is likely to be higher.

A second study by Murphy et al. 72 examined the association between residual blockade and critical respiratory events in a large sample of patients (n = 7459). Of 61 patients with a respiratory event, 42 were matched with control patients without an event. Thirty-one of the cases (73.8%) and none of the control patients had a TOF ratio of < 0.7 on arrival in the postanaesthesia care unit. This study is significant because it suggests that improvements in the effectiveness of reversal as measured by TOF monitoring may be associated with a decrease in important adverse events occurring in the immediate postoperative period. In contrast, Berg et al. 45 found no significant difference in rates of postoperative pulmonary complications (evaluated 2–6 days after surgery) between patients with and without residual blockade for patients treated with vecuronium or atracurium.

Anaphylactic and allergic reactions

Six studies provided data on rates of anaphylactic reactions to NMBAs (Table 25): four national surveys64,66,67,70 and two single-centre surveys. 68,73 Only one of these studies, a single-centre survey, provided a rate based on a known number of patients and even this was approximate: Malinowsky et al. 68 reported 6 cases of anaphylaxis among approximately 70,000 exposures, a rate of 1/11,667. Three cases were attributed to succinylcholine and one each to rocuronium, atracurium and cisatracurium. However, this study did not provide data on the number of exposed patients for individual agents.

Two national surveys have examined anaphylactic reactions to NMBAs in France. 67,70 In these studies, the number of patients exposed to each agent was estimated from data on market share and agents were compared based on the ratio of percentage total reactions–percentage market share. The value of these data in estimating risk of anaphylactic reactions is thus limited, although both surveys showed that rocuronium and succinylcholine had high ratios of anaphylactic reactions to market share (2.92 and 4.9 for rocuronium, and 3.05 and 3.37 for succinylcholine). The other NMBAs evaluated had ratios of 1 or less.

A survey reporting data from Scandinavian countries found 29 cases of anaphylaxis among an estimated (from sales data) 150,000 patients exposed to rocuronium, a rate of 1/5000 (95% CI: 1/3600 to 1/7700). However, rates from other Scandinavian countries were substantially lower: 95% CIs of 1/28,000 to 0 in Sweden, 1/45,000 to 0 in Denmark, and 1/32,000 to 1/350,000 in Finland. 66 For vecuronium, the rate of anaphylactic reactions in Norway was estimated to be 1/22,000 (95% CI: 1/7400 to 1/105,000). The authors of this study suggested that differences between countries were probably caused by differences in reporting. This is in line with the conclusion of Malinowsky et al. 68 that careful follow-up of adverse reactions increases the incidence of anaphylactic reactions reported.

A survey in the USA found 33 reports of adverse events that could indicate anaphylaxis to rocuronium and 20 to vecuronium; rates per number of vials sold were around 1/1,000,000. 64 The value of this study was limited by the fact that actual patient numbers were not used and that suspected anaphylactic reactions were not followed up.

A single-centre survey in the UK found three confirmed anaphylactic reactions to rocuronium among an estimated 8800 exposed patients over 2 years, a rate of approximately 1/3000. 73 This is in line with the data from Norway, although the UK data are limited by being from a single hospital and based on estimated rather than actual patient numbers.

A study of the UK yellow card reporting system based on data for 1967–2000 reported more allergic reactions to atracurium (151) and succinycholine (165) than to vecuronium or mivacurium (45 each). 62 However, these data are limited by not knowing the number of exposed patients.

The limited data available thus suggest that around 1/10,000 exposed patients may show an anaphylactic reaction to NMBA treatment, although the level of uncertainty is high. 66,73

Residual blockade/recurrence of blockade

Patients with butyrylcholinesterase deficiency are at risk of prolonged NMB after treatment with succinylcholine. A non-systematic review74 estimated that the frequency of this enzyme deficiency in the population is 1/2886 (95% CI 1/4327 to 1/1967).

Cardiac arrest

A non-systematic review74 provided estimates of rates of cardiac arrest associated with succinylcholine. In three large observational studies there were 21 cases of cardiac arrest among 457,609 patients, giving an overall rate of 1/21,970. However, the upper and lower limits of the 95% CI were taken to be 0 and 1/11,930 because all of the observed cardiac arrests occurred in one study (n = 250,541).

Malignant hyperthermia

Malignant hyperthermia is a rare but potentially dangerous event in genetically susceptible people treated with succinylcholine. A non-systematic review74 reported the risk of hyperthermia associated with succinylcholine as 1/96,046 (95% CI: 1/302,755 to 1/41,442). This is in line with the overall risk of hyperthermia in anaesthesia quoted by Rosenberg et al. 75 of between 1/5000 and 1/100,000. The same review75 reports the estimated incidence of genetic susceptibility to malignant hyperthermia to be between 1/3000 and 1/8500.

Myalgia

Succinylcholine-associated myalgia is a relatively minor adverse effect that affects patient QoL and can last for several days. In a systematic review of interventions to prevent myalgia, the incidence of myalgia at 24 hours after surgery in patients who received succinylcholine with no treatment to reduce myalgia was 51% (range 10–83%) across 35 trials. 76

Strategies

The strategies considered for routine NMB and subsequent reversal were limited by the available data; as such, a number of the comparators listed in Table 2 (atracurium, cisatracurium and mivacurium) were not considered.

The strategies considered were as follows:

• rocuronium (0.6 mg/kg)-induced NMB followed by reversal using neostigmine (2.5 mg) with glycopyrrolate (0.5 mg) (hereafter referred to as ‘rocuronium with N&G’)

• rocuronium (0.6 mg/kg)-induced NMB followed by reversal using sugammadex (2 mg/kg or 4 mg/kg) (hereafter referred to as ‘rocuronium with sugammadex’)

• vecuronium (0.1 mg/kg)-induced NMB followed by reversal using neostigmine (2.5 mg) with glycopyrrolate (0.5mg) (hereafter referred to as ‘vecuronium with N&G’)

• vecuronium (0.1 mg/kg)-induced NMB followed by reversal using sugammadex (2 mg/kg or 4 mg/kg) (hereafter referred to as ‘vecuronium with sugammadex’).

The routine reversal of moderate blockade was considered separately from that of profound (deep) blockade. It was assumed that a dosage of 2 mg/kg of sugammadex would be used in the former scenario and a dosage of 4 mg/kg would be used in the latter scenario, as per the manufacturer’s recommendations. 89

Owing to the lack of suitable evidence it was decided that a full incremental analysis of all possible strategies was not suitable. Rather, pairwise threshold analyses were undertaken comparing:

• rocuronium with sugammadex versus rocuronium with N&G

• vecuronium with sugammadex versus vecuronium with N&G.

These strategies and those considered in the rapid sequence induction (RSI) setting (see Reversal of NMB used in the RSI setting) are summarised in the decision tree given in Figure 2.

FIGURE 2.

Summary of strategies considered in the routine and RSI settings.

Key economic considerations and assumptions

To simplify the economic modelling, it was assumed that the choice of NMBA or reversal agent had no impact on surgery itself (time spent in surgery, adverse events resulting from surgery, etc.) or on the staff mix in the operating room. It was assumed that the anaesthetist was equally proficient at administering each strategy.

The possible drivers for differences between the costs and health outcomes of each strategy were identified as the following:

• the cost of acquiring rocuronium, vecuronium, N&G and sugammadex

• time spent in recovery

• rates of serious adverse events (including death) associated with the anaesthetic strategies

• rates of recurrence of blockade or residual blockade associated with the anaesthetic strategies.

The aim of the modelling was to integrate as many of these possible drivers as was feasible, given the evidence constraints faced. The general framework was to use threshold and sensitivity analysis to assess what combination of price and clinical parameters for sugammadex would be consistent with the new intervention being cost-effective if used as an alternative to an existing anaesthetic strategy.

Prices

The prices for rocuronium (Esmeron; Organon), vecuronium (Norcuron; Organon) and N&G (Robinul-Neostigmine; Anpharm) were taken from the British National Formulary56.

Cost per average dose was calculated on the assumptions that:

• the average patient had a weight of 75 kg

• the cheapest combination of vials specified by the BNF was used

• any unused drug in a vial was wasted.

The assessment group was made aware of the list prices by the manufacturer: 10 × 2-ml vials £596.40; 10 × 5-ml vials £1491.00; 100 mg of sugammadex per millilitre. For an average 75-kg patient, reversal of moderate blockade with 2 mg/kg of sugammadex therefore requires one 2-ml vial (£59.64), whereas reversal of profound blockade with 4 mg/kg of sugammadex requires two 2-ml vials (£119.28).

The costs per dose used in the model are given in Table 26.

Time spent in recovery

A key difference between sugammadex and existing anaesthetic strategies is the time it takes a patient to recover from the NMB. It was assumed that time to TOF 0.9 was a meaningful measure of time to recovery in routine practice, and that any reduction in recovery time achieved through adopting sugammadex could potentially represent a resource saving to the NHS if the member(s) of staff monitoring patients’ recovery could put the time saved to productive use.

As reported in Chapter 3 (see Results of review of clinical effectiveness), two active-controlled trials29,30 compared sugammadex versus N&G for the reversal of moderate block, while one active-controlled trial36 compared sugammadex versus N&G for the reversal of profound block. The results from Flockton et al. 29 were unsuitable as the study compared rocuronium with sugammadex against cisatracurium with N&G, which is not considered as a comparator in the economic analysis.

Blobner et al. 30 and Jones et al. 36 reported the median and geometric mean times for recovery to TOF 0.9 for rocuronium with sugammadex compared to rocuronium with N&G, and for vecuronium with sugammadex compared with vecuronium with N&G. These are reported in Tables 6 and 12. In order to estimate the arithmetic mean times to recovery in each instance (necessary to estimate the time saved), it was assumed that the distribution of recovery times was approximately exponential, such that the arithmetic mean time to recovery was the inverse of the baseline hazard, derived by dividing –ln(0.5) by the median time to recovery. 36,90

In each of the pairwise comparisons, the sugammadex strategy was associated with the shorter arithmetic mean time to recovery. As such, the model considered the reduction in recovery time associated with sugammadex. These are reported in Table 27.

Given the uncertainty and the anticipated heterogeneity around these estimates, the time spent in recovery was modelled as a variable taking values from 0 to 90 minutes inclusive.

It was assumed that any reduction in recovery time by adopting sugammadex would result in productivity benefits for the NHS. Since the value of these productivity benefits are subject to considerable uncertainty, the per-minute value of reductions in recovery time was modelled as a variable.

To aid discussion, two possible valuations of these productivity benefits were considered and are presented with the results: in the first, the value of each minute of recovery time saved was estimated as being the pro rata cost of employing the operating room staff (on the basis that all time savings would be achieved in the operating room); in the second, the value of each minute saved was estimated as the pro rata cost of employing a single nurse in the recovery room (on the basis that all time savings would be achieved in the recovery room).

Following expert clinical opinion it was assumed that the operating room staff comprised a consultant surgeon, a specialist registrar surgeon, a consultant anaesthetist, a nurse team manager (band 7) and two staff nurses (one band 5 and one band 6), while the recovery room nurse was assumed to be of band 5 (p = 0.75), band 6 (p = 0.125) or band 7 (p = 0.125). A potential criticism of these estimates is that they represent the opinion of a single clinical expert only. The cost associated with this time was calculated on a per-minute basis by taking the annual cost of employing each member of staff (including salary, national insurance and pension costs) from the Personal Social Services Research Unit91 (Table 28).

The major uncertainty is the extent to which any time saved in recovery could be put to alternative productive use, for example in caring for another patient or some other activity. The proportion of recovery time saved which could be put to productive use is ultimately unknown – no evidence was identified in the literature. There is also the possibility that extra operations could be scheduled as a result of any reduced recovery time but again there is a lack of suitable evidence on the associated impact on costs and health effects.

Serious adverse events

The clinical trials of sugammadex were not sufficiently powered to estimate the rates of significant adverse events (including death) with any level of precision, nor were there any observational data to inform these rates. As such, in the absence of clear evidence to the contrary, it was assumed that there were no differences in rates of adverse events between the strategies. This is a limitation of the modelling and should be considered when interpreting the results. In particular, the modelling assumed that in the routine setting there was no possibility of a difficult airway and/or ‘cannot intubate, cannot ventilate’ event occurring; while rare in this setting, the consequences of such an event may be extremely serious – this assumption will be returned to in the Discussion.

Recurrence of blockade or residual blockade

It was assumed that any incidence of recurrence of blockade, or residual blockade, in patients who had been considered to have recovered would represent a resource cost to the NHS. This is because additional time would have to be spent by the member(s) of staff monitoring the patients’ recovery. The incidence and cost of this event have been considered explicitly in the modelling. Following expert clinical opinion, it was assumed in the base case that patients suffering from recurrence of blockade or residual blockade were monitored by a single nurse of band 5 (p = 0.75), band 6 (p = 0.125) or band 7 (p = 0.125), and that the additional time associated with caring for a patient with recurrence of blockade or residual blockade was 1 hour. It was assumed that this time would be taken from other productive uses so its use had a value equal to the cost of employing the nurse over that period of time (calculated on a per-minute basis – Table 29). The additional hour of recovery time, therefore, represented a resource cost of £19.61.

Due to a lack of suitable evidence, it was assumed that there was no decrement in patients’ health-related quality of life (HRQoL) associated with recurrence of blockade or residual blockade. By implication, the health outcomes associated with each strategy were therefore assumed to be identical.

As discussed in Chapter 3 (see Summary of adverse effects of sugammadex), the manufacturer of sugammadex’s submission to the regulatory authority23 found that, in the phase III placebo-controlled trials for sugammadex, 1.7% of patients (11/640) had evidence of recurrence of blockade or residual blockade based on acceleromyographic monitoring. However, as the majority of these patients received subtherapeutic doses of sugammadex it was decided that this estimate was not appropriate for consideration in the model and so no residual blockade or recurrence of blockade was assumed for sugammadex.

The rates for other comparators were taken from RCTs reported in Tables 23 and 24. As these trials had no common comparator it was not possible to carry out an indirect comparison of the evidence. Rather, the rates used in the model were taken directly from the relevant treatment arm of each trial. Considerable care should, therefore, be taken when interpreting the results.

The rates of recurrence of blockade or residual blockade used in the model are reproduced in Table 30 along with the associated resource cost.

Analysis

Since the strategies were assumed to have identical health outcomes but generally different costs, the analysis effectively simplifies to a cost minimisation. Given the fact that particular variables are unknown, a threshold analysis was undertaken. The critical variables in this analysis were the reduction in recovery time by using sugammadex and the value of each minute of recovery time saved.

The threshold analysis sought to derive the minimum value of each minute of recovery time saved for sugammadex to be cost-effective (i.e. cost saving with equal health outcomes) at the current list price for any given (absolute) reduction in the recovery time associated with sugammadex.

Strategies

To simplify the modelling, it was assumed that rapid reversal of NMB would only be required in the case of a ‘cannot intubate–cannot ventilate’ event, in which case it was assumed that surgery would not be performed. Where a ‘cannot intubate–cannot ventilate’ event does not occur, it was assumed that surgery would proceed as usual, with the drugs and doses administered being dependent on the length of the procedure and/or whether the procedure requires profound blockade throughout.

As the differences in results between rocuronium- and vecuronium-induced blockade are so slight (see Results of economic assessment), and also because the 16-mg/kg dose of sugammadex is specifically indicated for reversal of rocuronium-induced blockade, only rocuronium-induced blockade was considered in the RSI setting.

The strategies considered for NMB and subsequent reversal are summarised below and also in Figure 2. The choice of strategy is dependant on the ex poste realisation of whether a ‘cannot intubate–cannot ventilate’ event occurs.

Where a ‘cannot intubate–cannot ventilate’ event occurs:

• succinylcholine (1 mg/kg)-induced NMB followed by spontaneous recovery (hereafter referred to as ‘succinylcholine’)

• rocuronium (1.2 mg/kg)-induced NMB followed by immediate reversal using 16-mg/kg sugammadex (hereafter referred to as ‘rocuronium with 16-mg/kg sugammadex’).

Where a ‘cannot intubate–cannot ventilate’ event does not occur and the subsequent procedure is very short:

• succinylcholine (1 mg/kg)-induced NMB (for rapid induction and to maintain block throughout the procedure) followed by spontaneous recovery (hereafter referred to as ‘succinylcholine’)

• rocuronium (1.2 mg/kg)-induced NMB (for rapid induction and to maintain block throughout the procedure) followed by reversal using 4-mg/kg sugammadex (hereafter referred to as ‘rocuronium with 4-mg/kg sugammadex’).

Where a ‘cannot intubate–cannot ventilate’ event does not occur and the subsequent procedure is short (< 60 minutes) or requires profound blockade throughout:

• succinylcholine (1 mg/kg)-induced NMB (for rapid induction) followed by rocuronium (0.6 mg/kg)-induced NMB (to maintain block throughout the procedure) followed by reversal using neostigmine (2.5 mg) with glycopyrrolate (0.5 mg) (hereafter referred to as ‘succinylcholine followed by rocuronium with N&G’)

• rocuronium (1.2 mg/kg)-induced NMB (for rapid induction and to maintain block throughout the procedure) followed by reversal using 4-mg/kg sugammadex (hereafter referred to as ‘rocuronium with 4-mg/kg sugammadex’).

Where a ‘cannot intubate–cannot ventilate’ event does not occur and the subsequent procedure is long (> 60 minutes) and does not require profound blockade throughout:

• succinylcholine (1 mg/kg)-induced NMB (for rapid induction) followed by rocuronium (0.6 mg/kg)-induced NMB (to maintain block throughout the procedure) followed by reversal using neostigmine (2.5 mg) with glycopyrrolate (0.5 mg) (hereafter referred to as ‘succinylcholine followed by rocuronium with N&G’)

• rocuronium (1.2 mg/kg)-induced NMB (for rapid induction and to maintain block throughout the procedure) followed by reversal using 2-mg/kg sugammadex (hereafter referred to as ‘rocuronium with 2-mg/kg sugammadex’).

Key economic considerations and assumptions

As with the routine reversal of NMB, it was assumed that the choice of NMBA or reversal agent had no impact on surgery itself or on the staff mix in the operating room. It was assumed that the anaesthetist was equally proficient at administering each strategy.

The possible drivers for differences between the costs and health outcomes of each strategy were identified as the following:

• the cost of acquiring rocuronium, N&G, sugammadex and succinylcholine

• time spent in recovery

• rates of serious adverse events (including death) associated with the anaesthetic strategies

• rates of recurrence of blockade or residual blockade associated with the anaesthetic strategies.

Prices

The prices for rocuronium (Esmeron; Organon) and succinylcholine (Anectine; GlaxoSmithKline) were taken from the British National Formulary 56.

As in the routine setting, cost per average dose was calculated on the assumptions that:

• the average patient has a weight of 75 kg

• the cheapest combination of vials specified by the British National Formulary was used

• any unused drug in a vial was wasted.

As discussed in the routine setting, the assessment group was made aware of the list prices for sugammadex by the manufacturer (see Routine reversal of neuromuscular block). For an average 75-kg patient, rapid reversal of blockade with 16 mg/kg of sugammadex requires two 5-ml vials and one 2-ml vial (£357.84).

The costs per dose used in the model are given in Tables 26 and 32.

‘Cannot intubate–cannot ventilate’ events

It was considered that ‘cannot intubate–cannot ventilate’ events are more likely to occur in the RSI setting than in the routine setting, but that the probability of a ‘cannot intubate–cannot ventilate’ event occurring in any given procedure is highly variable, depending on patients’ characteristics, but clinical judgements about this risk can be made for individual patients. As such – unlike in the routine setting – ‘cannot intubate–cannot ventilate’ events were explicitly considered in the modelling of the RSI setting, with the probability of a ‘cannot intubate–cannot ventilate’ event modelled as a variable from 0 to 1 inclusive.

In the absence of any data to the contrary, it was assumed that there were no systematic differences between each strategy in terms of the direct or indirect health consequences of a ‘cannot intubate–cannot ventilate’ event, and that the only cost/resource differences between the strategies resulted from (1) differences in the acquisition cost of sugammadex and rocuronium compared with succinylcholine, and (2) the negation of any potential productivity benefits from sugammadex (due to reduced recovery time) that may have arisen had the procedure gone ahead. These assumptions are returned to in the discussion.

Other serious adverse events

The clinical review identified a number of adverse events associated with succinylcholine (see Chapter 3, Adverse effects of succinylcholine). However, there was an absence of evidence to inform the expected costs and HRQoL decrements associated with adverse events other than death. As such, these were not considered in the base-case analysis.

An attempt was made to estimate the expected costs incurred by the NHS due to succinylcholine-related morbidity in order to inform further discussion. From expert opinion, it was assumed that 1 in every 1000 patients administered with succinylcholine would require a single additional day in hospital as a result of an adverse event directly attributable to succinylcholine. An estimate of the cost to the NHS of this additional day in hospital was derived from the National Schedule of Reference Costs 2006/07 for NHS Trusts92 by taking a weighted average of the national average unit cost for an excess bed-day across all surgery-related health-care resource group (HRG) codes (for both elective and non-elective procedures), with the weights corresponding to the number of excess bed days associated with each code; this cost was estimated to be £252.27 or £0.25 per patient administered with succinylcholine. Furthermore, the assessment group received expert clinical advice that approximately 1 in every 100 patients administered with succinylcholine would contact their local primary care centre in response to a succinylcholine-related adverse event. Whilst the cost to the NHS of this contact with primary care is difficult to estimate, it is perhaps reasonable to assume that the expected cost per patient administered with succinylcholine would not be significantly greater than that associated with the possibility of an excess bed-day.

Clinical trials have not established any effect on mortality associated with sugammadex (see Chapter 3), although it is possible that such trials were not sufficiently powered to do so. Whilst there is a paucity of evidence linking succinylcholine directly to rates of mortality, expert clinical opinion suggests that the most likely cause of mortality in patients who are administered succinylcholine was cardiac arrest. As reported in Chapter 3 (see Adverse effects of succinylcholine), the non-systematic review by Dexter et al. 74 provided estimates of rates of cardiac arrest associated with succinylcholine: in three large observational studies there were 21 cases of cardiac arrest among 457,609 patients, giving an overall rate of 1/21,970. As not all cardiac arrests are fatal, the average rate of mortality across all patients may be expected to be lower than this, although it is likely that the rate of mortality is highly heterogeneous and may be substantially higher in some groups of patients (e.g. the elderly and/or seriously ill). Schwartz et al. 93 (cited in Smith94) reported that, in 238 critically ill patients, emergency intubation was associated with a 3% rate of death within 30 minutes of intubation; it is unknown how many of those deaths could be attributed directly to succinylcholine.

Given the lack of suitable data on mortality with existing anaesthetic regimens, it was decided that the baseline probability of mortality associated with succinylcholine should be modelled as an unknown variable. It was assumed that the risk of mortality with sugammadex would be relatively lower than that for succinylcholine, and various scenarios were explored where this relative risk took a value of zero (mortality risk removed with sugammadex), 0.25 (75% risk reduction), 0.50 (50% risk reduction) or 0.75 (25% risk reduction). It was assumed that this baseline probability of mortality associated with succinylcholine was independent of the probability of a ‘cannot intubate–cannot ventilate’ event occurring.

It was assumed that deaths resulting from succinylcholine incurred no additional costs but resulted in forgone QALYs. These were calculated for patients aged 20 or 60 years by taking their expected survival duration from the most recent national mortality data for England and Wales (National Statistics 200895), weighing each year of life forgone according to the HRQoL indexes published in Kind et al. 96 (Table 33). These forgone QALYs were discounted at 3.5% per annum to calculate the discounted, quality-adjusted life expectancy of patients of each age (representing the QALYs forgone in the event of death) (Table 34).

Recurrence of blockade or residual blockade

It was assumed that there was no residual blockade or recurrence of blockade with sugammadex or succinylcholine.

Analysis

As the strategies were assumed to have generally different expected costs and health outcomes, a cost-effectiveness analysis was carried out in the form of a threshold analysis. Critical variables included the probability of a ‘cannot intubate, cannot ventilate’ event occurring, the baseline probability of mortality of succinylcholine, the relative risk of mortality of adopting sugammadex, the age of the patient (and hence the QALYs forgone in the case of death) and (where a ‘cannot intubate, cannot ventilate’ event does not occur) the number of minutes of recovery time saved by adopting sugammadex and the value of each minute saved.

It was assumed that each minute of recovery time saved through using sugammadex was valued either at £4.44 (on the basis that all time savings would be in the operating room) or £0.33 (on the basis that all time savings would be in the recovery room) (see Routine reversal of neuromuscular block) and that the amount of recovery time saved for each procedure was 23.37 minutes for reversal of moderate blockade, and 66.80 minutes for reversal of profound blockade (Table 27). The cost-effectiveness threshold, used to value QALYs forgone in monetary terms, was assumed to be £20,000 per QALY following the NICE methods guidance. 97

The analysis sought to derive the minimum baseline probability of death directly due to succinylcholine for sugammadex to be considered cost-effective for any given probability of a ‘cannot intubate–cannot ventilate’ event.

Annual Meeting of the European Society of Anaesthesiology (Euroanaesthesia Congress)

• www.euroanesthesia.org/

• 2008 Copenhagen, Denmark.

• Previous conference abstracts available in the European Journal of Anaesthesiology:

  1. – 2007;24(Suppl. 39). Munich, Germany, 9–12 June 2007

  2. – 2006;23(Suppl. 37). Madrid, Spain, 3–6 June 2006

  3. – 2005;22(Suppl. 34). Vienna, Austria, 28–31 May 2005

  4. – 2004;21(Suppl. 32). Lisbon, Portugal, 5–8 June 2004.

American Society of Anesthesiologists Annual Meeting (2001–8)

• www.asaabstracts.com/strands/asaabstracts/home.htm

• Searchable archive available for meetings 2001–8.

Association of Anaesthetists of Great Britain & Ireland Annual Congress (2004–7)

• www.aagbi.org/

• Congress programmes available online. 2005 and 2006 congress ‘free’ abstracts available in Anaesthesia 2006;61(1):80–94, 2005;60(3):302–17.

World Federation of Societies of Anaesthesiologists

• www.anaesthesiologists.org/

• 14th World Congress of Anaesthesiologists (WCA). 2008 Cape Town, South Africa, 2–7 March 2008.

MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations (OvidSP), 1998–2008/October week 3: 23 October 2008

895 records were retrieved in MEDLINE and 132 in MEDLINE In-Process & Other Non-Indexed Citations.

1. exp *Neuromuscular Blocking Agents/ae [Adverse Effects]

2. rocuronium.mp. and ae.fs.

3. Vecuronium Bromide/ae [Adverse Effects]

4. Atracurium/ae [Adverse Effects]

5. cisatracurium.mp. and ae.fs.

6. mivacurium.mp. and ae.fs.

7. Neostigmine/ae [Adverse Effects]

8. Glycopyrrolate/ae [Adverse Effects]

9. Succinylcholine/ae [Adverse Effects]

10. or/1–9

11. exp *Neuromuscular Blocking Agents/

12. rocuronium.mp.

13. *Vecuronium Bromide/

14. *Atracurium/

15. cisatracurium.mp.

16. mivacurium.mp.

17. *Neostigmine/

18. glycopyrrolate.mp.

19. (succinylcholine or suxamethonium).mp.

20. or/11–19

21. (adverse or side effect$).ti,ab.

22. Flushing/or skin flush.ti,ab.

23. Erythema/or erythema$.ti,ab.

24. Pruritis/or (pruritis or pruritus or itching).ti,ab.

25. Urticaria/or (urticaria$or hives).ti,ab.

26. Respiratory Sounds/or Wheezing.ti,ab.

27. Hypotension/or hypotensi$.ti,ab.

28. Bronchial Spasm/or (bronchospasm$or bronchial spasm$).ti,ab.

29. Cyanosis/or (cyanosis or cyanoses).ti,ab.

30. Hypersensitivity/or (hypersensitivit$or allergy or allergies or allergic).ti,ab.

31. Heart Arrest/or (cardiac arrest or heart arrest or cardiopulmonary arrest or asystole$).ti,ab.

32. Seizures/or seizure$.ti,ab.

33. Anaphylaxis/or (anaphylaxis or anaphylactic or anaphylactoid).ti,ab.

34. Paralysis/or paralysis.ti,ab.

35. muscle pain.ti,ab.

36. (prolong$adj2 block$).ti,ab.

37. Intraocular Pressure/or (intraocular pressure$or ocular tension$).ti,ab.

38. Malignant Hyperthermia/or (malignant hyperthermia$or malignant hyperpyrexia$).ti,ab.

39. Hyperkalemia/or (hyperkalaemia$or hyperkalemia$or hyperpotassemia$).ti,ab.

40. Rhabdomyolysis/or (rhabdomyolysis or rhabdomyolyses).ti,ab.

41. Bradycardia/or (bradycardia$or bradyarrhythmia$).ti,ab.

42. “Postoperative Nausea and Vomiting”/or (postoperative adj (nausea or vomiting or emesis or emeses)).ti,ab.

43. or/21–42

44. 20 and 43

45. 10 or 44

46. humans/

47. 45 and 46

48. limit 47 to (english language and yr = “1998 – 2008”)

49. (comment or news or editorial or letter).pt.

50. 48 not 49

MEDLINE In-Process & Other Non-Indexed Citations search strategy

1. (neuromuscular block$).mp

2. rocuronium.mp.

3. vecuronium.mp.

4. atracurium.mp.

5. cisatracurium.mp.

6. mivacurium.mp.

7. neostigmine.mp.

8. glycopyrrolate.mp.

9. (succinylcholine or suxamethonium).mp.

10. or/1–9

11. (adverse or side effect$).mp

12. (flushing or skin flush).mp

13. erythema$.mp

14. (pruritis or pruritus or itching).mp

15. (urticaria$or hives).mp

16. wheezing.mp

17. hypotensi$.mp

18. (bronchospasm$or bronchial spasm$).mp

19. (cyanosis or cyanoses).mp

20. (hypersensitivit$or allergy or allergies or allergic).mp

21. (cardiac arrest or heart arrest or cardiopulmonary arrest or asystole$).mp

22. seizure$.mp

23. (anaphylaxis or anaphylactic or anaphylactoid).mp

24. muscle pain.mp

25. (prolong$adj2 block$).mp

26. paralysis.mp

27. (intraocular pressure$or ocular tension$).mp

28. (malignant hyperthermia$or malignant hyperpyrexia$).mp

29. (hyperkalaemia$or hyperkalemia$or hyperpotassemia$).mp

30. (rhabdomyolysis or rhabdomyolyses).mp

31. (bradycardia$or bradyarrhythmia$).mp

32. (postoperative adj (nausea or vomiting or emesis or emeses)).mp

33. or/11–32

34. 10 and 33

EMBASE (OvidSP), 1998–2008/week 42: 23 October 2008

800 records were retrieved.

1. *Neuromuscular Blocking Agent/ae [Adverse Drug Reaction]

2. *ROCURONIUM/ae [Adverse Drug Reaction]

3. *VECURONIUM/ae [Adverse Drug Reaction]

4. *ATRACURIUM/ae [Adverse Drug Reaction]

5. *CISATRACURIUM/ae [Adverse Drug Reaction]

6. *MIVACURIUM/ae [Adverse Drug Reaction]

7. *NEOSTIGMINE/ae [Adverse Drug Reaction]

8. *Glycopyrronium Bromide/ae [Adverse Drug Reaction]

9. *Suxamethonium/ae [Adverse Drug Reaction]

10. or/1–9

11. exp *Neuromuscular Blocking Agent/

12. *ROCURONIUM/

13. *VECURONIUM/

14. *ATRACURIUM/

15. *CISATRACURIUM/

16. *MIVACURIUM/

17. *NEOSTIGMINE/

18. *Glycopyrronium Bromide/

19. *Suxamethonium/

20. or/11–19

21. Side Effect/or (adverse or side effect$).ti,ab.

22. Flushing/or skin flush.ti,ab.

23. Erythema/or erythema$.ti,ab.

24. Pruritis/or (pruritis or pruritus or itching).ti,ab.

25. Urticaria/or (urticaria$or hives).ti,ab.

26. Wheezing/or wheezing.ti,ab.

27. Hypotension/or hypotensi$.ti,ab.

28. Bronchospasm/or (bronchospasm$or bronchial spasm$).ti,ab.

29. Cyanosis/or (cyanosis or cyanoses).ti,ab.

30. Allergy/or (hypersensitivit$or allergy or allergies or allergic).ti,ab.

31. Heart Arrest/or (cardiac arrest or heart arrest or cardiopulmonary arrest or asystole$).ti,ab.

32. Seizures/

33. Seizure/or seizure$.ti,ab.

34. Anaphylaxis/or (anaphylaxis or anaphylactic or anaphylactoid).ti,ab.

35. muscle pain.ti,ab.

36. (prolong$adj2 block$).ti,ab.

37. Paralysis/or paralysis.ti,ab.

38. Intraocular Pressure/or (intraocular pressure$or ocular tension$).ti,ab.

39. Malignant Hyperthermia/or (malignant hyperthermia$or malignant hyperpyrexia$).ti,ab.

40. Hyperkalemia/or (hyperkalaemia$or hyperkalemia$or hyperpotassemia$).ti,ab.

41. Rhabdomyolysis/or (rhabdomyolysis or rhabdomyolyses).ti,ab.

42. Bradycardia/or (bradycardia$or bradyarrhythmia$).ti,ab.

43. Postoperative Nausea/or (postoperative adj (nausea or vomiting or emesis or emeses)).ti,ab.

44. or/21–43

45. 20 and 44

46. 10 or 45

47. Animal/or Animal Experiment/or Nonhuman/

48. (rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow or bovine or sheep or ovine or monkey or monkeys).ti,ab,sh.

49. 47 or 48

50. exp Human/or Human Experiment/

51. 49 not (49 and 50)

52. 46 not 51

53. limit 52 to (english language and yr = “1998 – 2008”)

54. (editorial or letter).pt.

55. 53 not 54

TOXLINE (TOXNET – US National Library of Medicine), 2008/23 October: 23 October 2008

559 records were retrieved.

1. #1 “neuromuscular blocking agents” [ti] AND 1998:2008 [yr] AND (eng [la])

2. #2 (rocuronium OR zemuron)[ti] AND 1998:2008 [yr] AND (eng [la])

3. #3 vecuronium [ti] AND 1998:2008 [yr] AND (eng [la])

4. #4 (atracurium)[ti] AND 1998:2008 [yr] AND (eng [la])

5. #5 (cisatracurium)[ti] AND 1998:2008 [yr] AND (eng [la])

6. #6 (mivacurium) [ti] AND 1998:2008 [yr] AND (eng [la])

7. #7 (neostigmine OR prostigmine OR prostigmin OR eustigmine OR eustigmin) [ti] AND 1998:2008 [yr] AND (eng [la])

8. #8 (glycopyrrolate OR robinul OR “robinul forte” OR “glycopyrronium bromide”) [ti] AND 1998:2008 [yr] AND (eng [la])

9. #9 (succinylcholine OR “succinylcholine chloride” OR anectine OR quelicin OR “suxamethonium chloride” OR 71–27–2 [rn]) OR (suxamethonium OR 55–94–7 [rn])) [ti] AND 1998:2008 [yr] AND (eng [la])

10. #10 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9)

NHS EED (Cochrane Library), 2008 – Issue 2: 14 August 2008

35 records were retrieved.

1. #1 MeSH descriptor Neuromuscular Nondepolarizing Agents explode all trees

2. #2 (neuromuscular or “neuro muscular”) NEAR/2 (block* or agent*):ti,ab,kw

3. #3 (nondepolarizing or non-depolarizing or “non depolarizing” or nondepolarising or non-depolarising or “non depolarising”):ti,ab,kw

4. #4 (rocuronium* or esmeron* or zemuron*):ti,ab,kw

5. #5 MeSH descriptor Vecuronium Bromide explode all trees

6. #6 (vecuronium* or norcuron*):ti,ab,kw

7. #7 MeSH descriptor Atracurium explode all trees

8. #8 (atracurium* or tracrium*):ti,ab,kw

9. #9 (cisatracurium* or nimbex*):ti,ab,kw

10. #10 (mivacurium* or mivacron):ti,ab,kw

11. #11 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)

HEED (Wiley online), 2008/July: 14 August 2008

39 records were retrieved.

• AX = (neuromuscular block) or (neuromuscular blocking) or (neuromuscular agent) or neuromuscular agents) or (neuro muscular block) or (neuro muscular blocking) or (neuro muscular agent) or (neuro muscular agents)

• AX = (nondepolarizing) or (non-depolarizing) or (non depolarizing) or (nondepolarising) or (non-depolarising) or (non depolarising)

• AX = (rocuronium or vecuronium or atracurium or cisatracurium or mivacurium)

• CS = 1 or 2 or 3

MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations (OvidSP), 1950–2008/August week 1: 14 August 2008

176 records were retrieved in MEDLINE and 9 in MEDLINE In-Process & Other Non-Indexed Citations.

1. economics/

2. exp “costs and cost analysis”/

3. economics, dental/

4. exp “economics, hospital”/

5. economics, medical/

6. economics, nursing/

7. economics, pharmaceutical/

8. (economic$or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).tw.

9. (expenditure$not energy).tw.

10. (value adj1 money).tw.

11. budget$.tw.

12. or/1–11

13. ((energy or oxygen) adj cost).ti,ab.

14. (metabolic adj cost).ti,ab.

15. ((energy or oxygen) adj expenditure).ti,ab.

16. or/13–15

17. 12 not 16

18. humans.sh.

19. 17 and 18

20. (letter or comment or editorial).pt.

21. 19 not 20

22. exp Neuromuscular Nondepolarizing Agents/

23. ((neuromuscular or neuro muscular) adj2 (block$or agent$)).ti,ab.

24. (nondepolarizing or non-depolarizing or non depolarizing or nondepolarising or non-depolarising or non depolarising).ti,ab.

25. rocuronium$.ti,ab,rn.

26. (esmeron$or zemuron$).ti,ab,rn.

27. Vecuronium Bromide/

28. vecuronium$.ti,ab,rn.

29. norcuron$.ti,ab,rn.

30. Atracurium/

31. atracurium$.ti,ab,rn.

32. tracrium$.ti,ab,rn.

33. cisatracurium$.ti,ab,rn.

34. nimbex$.ti,ab,rn.

35. mivacurium$.ti,ab,rn.

36. mivacron$.ti,ab,rn.

37. or/22–36

38. 21 and 37

EMBASE (OvidSP), 1980–2008/week 32: 14 August 2008

179 records were retrieved.

1. Health Economics/

2. exp Economic Evaluation/

3. exp Health Care Cost/

4. exp PHARMACOECONOMICS/

5. or/1–4

6. (econom$or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab.

7. (expenditure$not energy).ti,ab.

8. (value adj2 money).ti,ab.

9. budget$.ti,ab.

10. or/6–9

11. 5 or 10

12. (metabolic adj cost).ti,ab.

13. ((energy or oxygen) adj cost).ti,ab.

14. ((energy or oxygen) adj expenditure).ti,ab.

15. or/12–14

16. 11 not 15

17. editorial.pt.

18. note.pt.

19. letter.pt.

20. or/17–19

21. 16 not 20

22. (rat or rats or mouse or mice or hamster or hamsters or animal or animals or dogs or dog or cats or bovine or sheep).ti,ab,sh.

23. exp animal/

24. Nonhuman/

25. or/22–24

26. exp human/

27. exp human experiment/

28. 26 or 27

29. 25 not (25 and 28)

30. 21 not 29

31. exp Neuromuscular Blocking Agent/

32. ((neuromuscular or neuro muscular) adj2 (block$or agent$)).ti,ab.

33. (nondepolarizing or non-depolarizing or non depolarizing or nondepolarising or non-depolarising or non depolarising).ti,ab.

34. Rocuronium/

35. rocuronium$.ti,ab,rn.

36. (esmeron$or zemuron$).ti,ab,rn.

37. Vecuronium/

38. vecuronium$.ti,ab,rn.

39. norcuron$.ti,ab,rn.

40. Atracurium/

41. atracurium$.ti,ab,rn.

42. tracrium$.ti,ab,rn.

43. Cisatracurium/

44. cisatracurium$.ti,ab,rn.

45. nimbex$.ti,ab,rn.

46. Mivacurium/

47. mivacurium$.ti,ab,rn.

48. mivacron$.ti,ab,rn.

49. or/31–48

50. Cholinesterase Inhibitor/

51. (cholinesterase$inhibitor$or anticholinesterase$or anti-cholinesterase$or acetylcholinesterase$inhibitor$).ti,ab.

52. Neostigmine/

53. neostigmine$.ti,ab,rn.

54. prostigmin$.ti,ab,rn.

55. (proserine$or prozerin$or synstigmin$or polstigmine$or syntostigmine$).ti,ab,rn.

56. (reverse or reverses or reversal or reversed or reversing or reversible).ti,ab.

57. or/50–56

58. Anesthetic Recovery/

59. (recover$adj3 an?esthes$).ti,ab.

60. (recover$adj3 (neuromuscular or block$)).ti,ab.

61. (recover$adj3 spontaneous).ti,ab.

62. ((neuromuscular or neuro muscular) adj3 antago$).ti,ab.

63. (muscle relax$adj3 antago$).ti,ab.

64. (residual paralysis or residual paresis).ti,ab.

65. (residual adj2 (neuromuscular or neuro muscular)).ti,ab.

66. residual curari$.ti,ab.

67. or/58–66

68. 30 and 49 and (57 or 67)

CINAHL (OvidSP), 1982–2008/August week 2: 14 August 2008

4 records were retrieved.

1. exp “costs and cost analysis”/or “economic aspects of illness”/or “economic value of life”/or economics, pharmaceutical/

2. ((cost or costs or costed or costly or costing) adj (utilit$or benefit$or effective$or stud$or minimi$or analys$)).ti,ab.

3. (economic$or pharmacoeconomic$or price$or pricing).ti,ab.

4. (expenditure$not energy).ti,ab.

5. (value adj1 money).ti,ab.

6. budget$.ti,ab.

7. or/1–6

8. exp Neuromuscular Nondepolarizing Agents/

9. ((neuromuscular or neuro muscular) adj2 (block$or agent$)).ti,ab.

10. (nondepolarizing or non-depolarizing or non depolarizing or nondepolarising or non-depolarising or non depolarising).ti,ab.

11. rocuronium$.ti,ab.

12. (esmeron$or zemuron$).ti,ab.

13. Vecuronium Bromide/

14. vecuronium$.ti,ab.

15. norcuron$.ti,ab.

16. ATRACURIUM/

17. atracurium$.ti,ab.

18. tracrium$.ti,ab.

19. cisatracurium$.ti,ab.

20. nimbex$.ti,ab.

21. mivacurium$.ti,ab.

22. mivacron$.ti,ab.

23. or/11–22

24. 7 and 23

Science Citation Index (Web of Science), 1900–2008/9 August: 14 August 2008

163 records were retrieved.

1. #1 TS = (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic*)

2. #2 TS = (value SAME money)

3. #3 TS = budget*

4. #4 TS = (expenditure* NOT energy)

5. #5 #1 OR #2 OR #3 OR #4

6. #6 TS = (neuromuscular or “neuro muscular”) SAME TS = (block* or agent*)

7. #7 TS = (nondepolarizing or non-depolarizing or “non depolarizing” or nondepolarising or non-depolarising or “non depolarising”)

8. #8 TS = (rocuronium* or esmeron* or zemuron*)

9. #9 TS = (vecuronium* or norcuron*)

10. #10 TS = (atracurium* or tracrium*)

11. #11 TS = (cisatracurium* or nimbex*)

12. #12 TS = (mivacurium* or mivacron*)

13. #13 #6 or #7 or #8 or #9 or #10 or #11 or #12

14. #14 #5 AND #13

CENTRAL (Cochrane Library), 2008 – Issue 3: 14 August 2008

90 records were retrieved.

1. #1 MeSH descriptor Neuromuscular Nondepolarizing Agents explode all trees

2. #2 (neuromuscular or “neuro muscular”) NEAR/2 (block* or agent*):ti,ab,kw

3. #3 (nondepolarizing or non-depolarizing or “non depolarizing” or nondepolarising or non-depolarising or “non depolarising”):ti,ab,kw

4. #4 (rocuronium* or esmeron* or zemuron*):ti,ab,kw

5. #5 MeSH descriptor Vecuronium Bromide explode all trees

6. #6 (vecuronium* or norcuron*):ti,ab,kw

7. #7 MeSH descriptor Atracurium explode all trees

8. #8 (atracurium* or tracrium*):ti,ab,kw

9. #9 (cisatracurium* or nimbex*):ti,ab,kw

10. #10 (mivacurium* or mivacron):ti,ab,kw

11. #11 (#18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26)

12. #12 MeSH descriptor Economics, this term only

13. #13 MeSH descriptor Costs and Cost Analysis explode all trees

14. #14 MeSH descriptor Economics, Medical explode all trees

15. #15 MeSH descriptor Economics, Pharmaceutical explode all trees

16. #16 (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic*):ti,ab,kw

17. #17 (expenditure* not energy):ti,ab,kw

18. #18 (value NEAR/3 money):ti,ab,kw

19. #19 (budget*):ti,ab,kw

20. #20 (#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19)

21. #21 (#11 AND #20)

ISI Proceedings: Science & Technology (Web of Science), 1990–2008/9 August: 14 August 2008

22 records were retrieved.

1. #1 TS = (economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic*)

2. #2 TS = (value SAME money)

3. #3 TS = budget*

4. #4 TS = (expenditure* NOT energy)

5. #5 #1 OR #2 OR #3 OR #4

6. #6 TS = (neuromuscular or “neuro muscular”) SAME TS = (block* or agent*)

7. #7 TS = (nondepolarizing or non-depolarizing or “non depolarizing” or nondepolarising or non-depolarising or “non depolarising”)

8. #8 TS = (rocuronium* or esmeron* or zemuron*)

9. #9 TS = (vecuronium* or norcuron*)

10. #10 TS = (atracurium* or tracrium*)

11. #11 TS = (cisatracurium* or nimbex*)

12. #12 TS = (mivacurium* or mivacron*)

13. #13 #6 or #7 or #8 or #9 or #10 or #11 or #12

14. #14 #5 AND #13

Anaesthesia-controlled time: UK specific studies (line 20) and non-UK economic studies (line 38)

1. exp anesthesia/

2. Anesthesiology/

3. 1 or 2

4. “time and motion studies”/

5. Time Management/

6. “Appointments and Schedules”/

7. Workload/

8. or/4–7

9. 3 and 8

10. (an?esth$adj3 (time$or duration or schedul$)).ti,ab.

11. (an?esth$adj3 (turnover$or throughput or quick$or fast$or rapid$or short$)).ti,ab.

12. (an?esth$adj3 (workload or work load or productivity)).ti,ab.

13. or/10–12

14. 9 or 13

15. humans/

16. 14 and 15

17. exp Great Britain/

18. (united kingdom or great britain or uk or england or wales or Scotland or Ireland).ti,ab,in.

19. 17 or 18

20. 16 and 19

21. economics/

22. exp “costs and cost analysis”/

23. economics, dental/

24. exp “economics, hospital”/

25. economics, medical/

26. economics, nursing/

27. economics, pharmaceutical/

28. (economic$or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab.

29. (expenditure$not energy).ti,ab.

30. (value adj1 money).ti,ab.

31. budget$.ti,ab.

32. or/25–31

33. ((energy or oxygen) adj cost).ti,ab.

34. (metabolic adj cost).ti,ab.

35. ((energy or oxygen) adj expenditure).ti,ab.

36. or/33–35

37. 32 not 36

38. 16 and 37

TOF/NMBAs and utility values

1. exp Neuromuscular Nondepolarizing Agents/

2. ((neuromuscular or neuro muscular) adj2 (block$or agent$)).ti,ab.

3. (nondepolarizing or non-depolarizing or non depolarizing or nondepolarising or non-depolarising or non depolarising).ti,ab.

4. rocuronium$.ti,ab,rn.

5. (esmeron$or zemuron$).ti,ab,rn.

6. Vecuronium Bromide/

7. vecuronium$.ti,ab,rn.

8. norcuron$.ti,ab,rn.

9. Atracurium/

10. atracurium$.ti,ab,rn.

11. tracrium$.ti,ab,rn.

12. cisatracurium$.ti,ab,rn.

13. nimbex$.ti,ab,rn.

14. mivacurium$.ti,ab,rn.

15. mivacron$.ti,ab,rn.

16. or/1–15

17. Anesthesia Recovery Period/

18. (recover$adj3 an?esthes$).ti,ab.

19. (recover$adj3 (neuromuscular or block$)).ti,ab.

20. (recover$adj3 spontaneous).ti,ab.

21. (residual adj2 block$).ti,ab.

22. (residual paralysis or residual paresis).ti,ab.

23. (residual adj2 (neuromuscular or neuro muscular)).ti,ab.

24. residual curari$.ti,ab.

25. or/17–24

26. train-of-four.ti,ab.

27. TOF.ti,ab.

28. 27 or 26

29. (index of wellbeing or quality of wellbeing or qwb).ti,ab.

30. (multiattribute$health or multi attribute$health).ti,ab.

31. (health utilit$index or health utilit$indices).ti,ab.

32. (multiattribute$theor$or multi attribute$theor$or multiattribute$analys$or multi attribute$analys$).ti,ab.

33. (health utilit$scale$or classification of illness state$).ti,ab.

34. health state$utilit$.ti,ab.

35. (multiattribute$utilit$or multi attribute$utilit$).ti,ab.

36. health utilit$scale$.ti,ab.

37. (euro qual or eruo qol or eq-5d or eq5d or eq 5d or euroqual or euroqol).ti,ab.

38. (sf36 or sf 36).ti,ab.

39. (short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty six or short form thirtysix or short form thirty six).ti,ab.

40. (sf 6d or sf6d or short form 6d or shortform 6d or sf six$or shortform six$or short form six$).ti,ab.

41. hrqol.ti,ab.

42. hrql.ti,ab.

43. (health related quality adj2 life$).ti,ab.

44. or/29–43

45. 25 or 28 or 16

46. 45 and 44

Overlapping induction

1. (overlap$adj3 induction$).ti,ab.

2. (overlap$adj3 an?esth$).ti,ab.

3. 1 or 2

4. exp Great Britain/

5. (united kingdom or great britain or uk or england or wales or Scotland or Ireland).ti,ab,in.

6. 4 or 5

7. 6 and 3

Rapid intubation mortality rates

1. Intubation, Intratracheal/mo

2. Intubation, Intratracheal/and (Mortality/or Death/)

3. 1 or 2

4. (rapid intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

5. (rapid sequence intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

6. (rapid induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

7. (rapid sequence induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

8. (RSI and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

9. (emergency intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

10. (emergency sequence intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

11. (emergency induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

12. (emergency sequence induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

13. (early intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

14. (early sequence intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

15. (early induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

16. (early sequence induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

17. (crash intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

18. (crash sequence intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

19. (crash induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

20. (crash sequence induction and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

21. (emergency airway manag$and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

22. (emergency tracheal intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

23. (rapid tracheal intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

24. (emergency endotracheal intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

25. (rapid endotracheal intubation and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

26. (emergency tracheostomy and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

27. (rapid tracheostomy and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

28. (early tracheostomy and (mortality or mortalities or death or fatality or fatalities)).ti,ab.

29. or/3–28

30. Humans/

31. 29 and 30

32. (letter or comment or editorial).pt.

33. 31 not 32

34. exp Anesthesia/mo [Mortality]

35. Succinylcholine/and (exp Mortality/or exp Death/)

36. 30 and (34 or 35)

37. 36 not 32

38. 33 or 37