Anaesthesia 2012, 67, 991998

doi:10.1111/j.1365-2044.2012.07197.x

Original Article
A randomised controlled trial comparing sugammadex and
neostigmine at different depths of neuromuscular blockade in
patients undergoing laparoscopic surgery*
G. Geldner,1 M. Niskanen,2 P. Laurila,3 V. Mizikov,4 M. Hubler,5 G. Beck,6 H. Rietbergen7 and
E. Nicolayenko8
1 Professor, Department of Anaesthesiology, Klinikum Ludwigsburg, Academic Teaching Hospital, University of
Heidelberg, Ludwigsburg, Germany
2 Lecturer, Department of Anaesthesiology and Operative Services, Kuopio University Hospital, Kuopio, Finland
3 Lecturer, Department of Anaesthesiology and Intensive Care, Oulu University Hospital, Oulu, Finland
4 Professor, Department of Anaesthesiology, Petrovsky National Research Center of Surgery, Moscow, Russia
5 Professor, Department of Anaesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Carus,
Technical University Dresden, Dresden, Germany
6 Professor, Department of Anaesthesiology, Dr. Horst Schmidt Clinic, Wiesbaden, Germany
7 Principal Statistician, Merck Sharp and Dohme (MSD), Oss, the Netherlands
8 Professor, Department of Anaesthesiology, University Hospital #1, RRW, Moscow, Russia

Summary
Deep neuromuscular blockade during certain surgical procedures may improve operating conditions. Sugammadex can
be used to reverse deep neuromuscular blockade without waiting for spontaneous recovery. This randomised study
compared recovery times from neuromuscular blockade induced by rocuronium 0.6 mg.kg)1, using sugammadex
4 mg.kg)1 administered at 12 post-tetanic count (deep blockade) or neostigmine 50 lg.kg)1 (plus atropine 10 lg.kg)1)
administered at the re-appearance of the second twitch of a train-of-four stimulation (moderate blockade), in patients
undergoing laparoscopic surgery. The primary efcacy variable was the time from the start of
sugammadex neostigmine administration to recovery of the train-of-four ratio to 0.9. Patients receiving
sugammadex recovered 3.4 times faster than patients receiving neostigmine (geometric mean (95% CI) recovery
times of 2.4 (2.12.7) and 8.4 (7.29.8) min, respectively, p < 0.0001). Moreover, 94% (62 66) of sugammadex-treated
patients recovered within 5 min, vs 20% (13 65) of neostigmine-treated patients, despite the difference in the depth of
neuromuscular blockade at the time of administration of both drugs. The ability to provide deep neuromuscular
blockade throughout the procedure but still permit reversal at the end of surgery may enable improved surgical access
and an enhanced visual eld.
. ..............................................................................................................................................................

Correspondence to: G. Geldner

Email: goetz.geldner@kliniken-lb.de
*Presented in part at the Annual Meeting of the American Society of Anesthesiologists, San Diego, CA, USA, October 2010;
Networking World Anesthesia Convention, Rome, Italy, April 2011; and the Annual Meeting of the Canadian
Anesthesiologists Society, Toronto, Canada, June 2011.
Accepted: 16 April 2012

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991

Anaesthesia 2012, 67, 991998

Provision of deep neuromuscular blockade until the end

of an operation may be benecial during certain types of
surgery, such as laparoscopic procedures, with the
potential to improve surgical access and enhance the
visual eld. However, the extended effects of neuromuscular blocking drugs may lead to postoperative complications and or a risk of residual neuromuscular
paralysis in the post-anaesthesia care unit, which may
contribute to morbidity in patients recovering from
surgery [1, 2]. Rapid and reliable reversal of neuromuscular blockade at the end of surgery is therefore
desirable to enhance patient safety and comfort, and
this may potentially decrease the time spent in the
operating room and post-anaesthesia care unit.
In contrast to neostigmine, sugammadex (Bridion,
Merck Sharp and Dohme (MSD), Oss, the Netherlands)
has the potential to achieve reliable, complete and rapid
reversal of both moderate and deep rocuronium- and
vecuronium-induced neuromuscular blockade [36].
The aim of the current study was to compare the
recovery from rocuronium-induced neuromuscular
blockade when sugammadex was given at a post-tetanic
count of 12, with neostigmine given at the reappearance of the second twitch (T2) of a train-of-four (TOF)
stimulation in patients undergoing laparoscopic surgery
under propofol anaesthesia. Additional aims included
assessment of the safety proles of neostigmine and
sugammadex, as well as evaluating the duration of stay
in the operating room and post-anaesthesia care unit.

Methods
This was a randomised, active-controlled, parallelgroup, multicentre, safety-assessor-blinded trial in adult
patients undergoing laparoscopic surgery. The study was
conducted in accordance with the principles of Good
Clinical Practice and was approved by the appropriate
institutional review boards and regulatory agencies.
Inclusion criteria were: age 18 years; ASA physical
status 13; scheduled laparoscopic cholecystectomy or
appendectomy under general anaesthesia; and written,
informed consent. Exclusion criteria were: suspected
difcult tracheal intubation; disorder affecting neuromuscular blockade; known or suspected signicant renal
dysfunction; known or suspected severe hepatic dysfunction; history of malignant hyperthermia; allergy to
opioids, neuromuscular blocking drugs or other medi992

Geldner et al. | Sugammadex vs neostigmine at varying block

cations used during general anaesthesia; contra-indication to neostigmine and or atropine; pregnancy
(excluded both from medical history and by a human
chorionic gonadotropin test within 24 h of surgery in
women of childbearing age); and breastfeeding. Patients
who had already participated in another sugammadex
study and those who had participated in another clinical
study not pre-approved by the sponsor within 30 days
were also excluded.
Patients were randomly assigned to either sugammadex 4 mg.kg)1 or neostigmine 50 lg.kg)1 in
combination with atropine 10 lg.kg)1, using an online
randomisation list; this was created by Orcapharma
(Heesch, the Netherlands) using the software package
SAS (SAS Institute, Cary, NC, USA), in compliance
with international protocols.
Anaesthesia was induced and maintained using
intravenous propofol, together with opioids (most
frequently fentanyl) as required, the choice and dose
of which were decided by the responsible anaesthetist.
After induction of anaesthesia, neuromuscular monitoring was performed continuously at the adductor pollicis
muscle with acceleromyography (TOF-Watch SX,
Organon Ireland Ltd., a subsidiary of Merck and Co.,
Swords, Co. Dublin, Ireland), following calibration and
stabilisation of the signal as recommended by the
manufacturer. Each patient then received rocuronium
0.6 mg.kg)1, after which tracheal intubation was performed. Maintenance doses of rocuronium (0.1
0.2 mg.kg)1) were given as required clinically during
surgery. At the end of the surgical procedure and
according to the randomisation schedule, patients
received either sugammadex 4 mg.kg)1, administered
at a post-tetanic count of 12 (deep neuromuscular
blockade), or neostigmine 50 lg.kg)1 plus atropine
10 lg.kg)1, administered at the reappearance of the
second twitch (T2) on the TOF (moderate blockade).
The primary efcacy parameter was the time from
the start of sugammadex or neostigmine administration
to recovery of the TOF ratio to 0.9. The time from the
last dose of rocuronium to recovery of the TOF ratio to
0.9 was also recorded. Secondary outcome parameters
included safety and length of stay in the operating room
and post-anaesthesia care unit following administration
of the study drug. Safety was assessed by adverse events,
vital signs and physical examination; all subjective safety
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Geldner et al. | Sugammadex vs neostigmine at varying block

assessments (i.e. adverse events or serious adverse

events) were performed by a blinded safety assessor.
Patients were also assessed for clinical evidence of
residual neuromuscular blockade and or recurrence of
neuromuscular blockade, based on neuromuscular monitoring and clinical assessment. To maintain blinding,
the safety assessor was not involved in the randomisation process, was not present during anaesthesia and was
not involved in the preparation of trial medication. The
relationship between the number of risk factors (dened
according to Apfel et al. [7, 8]) and the occurrence of
postoperative nausea and vomiting (PONV) was also
assessed. Risk factors were female sex; previous history
of PONV; previous history of motion sickness; nonsmoking status; and postoperative administration of
opioids.
Ten study sites were enrolled: three in Russia; four in
Germany; two in Finland; and one in the UK. We aimed
to base the sample size calculation on the anticipated
differences between the groups with respect to length of
stay in theatre and the post-anaesthesia recovery unit.
However, no appropriate previous data on these times
were available at the time the study was designed.
Therefore, the sample size calculation was based on
detecting with 80% probability a difference between the
two treatments of half a standard deviation. Assuming a
drop-out rate of 7%, 70 patients per group were required.
All efcacy analyses were performed using intent-to-treat,
comprising all randomised patients who received sugammadex or neostigmine and had at least one efcacy
measurement. Missing times to recovery of the TOF ratio
to 0.9 were imputed for the primary analysis, consistent
with previous sugammadex studies [3, 5]. A supportive
analysis was performed using patients with available
recovery times only. The logarithm of the recovery times
were analysed using ANOVA. Log transformation was
applied as recovery times are known to follow an
approximately lognormal distribution. Consequently,
recovery times were summarised using geometric means
and associated 95% CI. Data related to the duration of stay
in the operating room and post-anaesthesia care unit were
compared between the two groups using ANOVA. Heart
rates were compared (post hoc) between the two groups
using a repeated measurements ANOVA. Statistical
testing was performed two-sided at a signicance level
of 0.05.
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Anaesthesia 2012, 67, 991998

Results
In total, 140 patients were assigned to sugammadex
(70) or neostigmine (70); four patients in the sugammadex group and three in the neostigmine group
did not receive the study drug. Two patients in the
neostigmine group were not included in the efcacy
analysis because of failure of the neuromuscular
monitoring device (Fig. 1). Baseline characteristics
were generally comparable between the two groups
(Table 1).
Data were imputed using a conservative approach
towards sugammadex for three patients in the sugammadex group and ve in the neostigmine group because the
time to recovery of the TOF ratio to 0.9 was not available.
Out of these, for two in the sugammadex group and four
in the neostigmine group, the TOF ratio did not reach
0.9; for the remaining two patients, the times were
considered unreliable due to either an unstable trace
(neostigmine group) or unsuccessful calibration (sugammadex group).
Patients in the sugammadex group recovered 3.4
times faster than patients in the neostigmine group;
geometric mean (95% CI) times to recovery of the TOF
ratio to 0.9 were 2.4 (2.12.7) vs 8.4 (7.29.8) min,
respectively, p < 0.0001. Analysing only patients with
available recovery times resulted in similar outcomes.
The majority (94%) of patients in the sugammadex
group (62 66) recovered within 5 min, compared to
20% (13 65) in the neostigmine group; 20 min had
elapsed before 94% (61 65) of neostigmine patients had
recovered despite neostigmines being administered at
the time of only moderate neuromuscular blockade
(Fig. 2). The geometric mean (95% CI) times from the
last dose of rocuronium to recovery were 13.3 (11.6
15.3) min in the sugammadex group vs 35.2 (30.840.2)
min in the neostigmine group (p < 0.0001).
Overall, patients in both groups spent a similar
amount of time in the operating room (Table 2).
However, tracheal extubation occurred earlier in the
sugammadex group compared with the neostigmine
group, with an estimated mean (95% CI) treatment
difference of )6.5 ()9.3 to )3.7) min, p < 0.0001. In
addition, the time difference between study drug
administration and when patients were judged to be
ready for discharge from the operating room was lower
in the sugammadex group. However, the total time
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Geldner et al. | Sugammadex vs neostigmine at varying block

Enrolment
Assessed for eligibility (n = 152)
Excluded (n = 12)
Not meeting inclusion criteria (n = 4)
Declined to participate (n = 4)
Other reasons (n = 4)
- surgery rescheduled (n = 3)
- subject not ready for surgery (n = 1)

Randomised (n = 140)

Allocation
Sugammadex 4.0 mg.kg1
Allocated to intervention (n = 70)
Received allocated intervention (n = 66)
Did not receive allocated intervention (n = 4)
- operation cancelled (n = 1)
- operation rescheduled for time unsuitable
for study team (n = 1)
- unable to calibrate TOF-Watch SX (n = 2)

Neostigmine 50 g.kg1 + atropine 10 g.kg1

Allocated to intervention (n = 70)
Received allocated intervention (n = 67)
Did not receive allocated intervention (n = 3)
- operation cancelled (n = 1)
- operation rescheduled for time unsuitable
for study team (n = 1)
- did not meet inclusion/exclusion criteria
(discovered after randomisation) (n = 1)

Follow-up
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)

Lost to follow-up (patient could not be

contacted) (n = 1)
Discontinued intervention (n = 0)

Analysis
Analysed
Efficacy population, intention to treat (n = 66)
Safety population, all subjects treated (n = 66)

Analysed
Efficacy population, intention to treat (n = 65)
- no efficacy measurements due to technical
difficulty with TOF-Watch SX (n = 2)
Safety population, all subjects treated (n = 67)

Figure 1 Flow of patients through the study.

Table 1 Baseline characteristics in patients randomised
to receive either sugammadex (deep neuromuscular
blockade) or neostigmine (moderate neuromuscular
blockade). Values are mean (SD) or number (proportion).

Age; years
Weight; kg
Height; cm
Women
Race
Black or African
White
ASA physical status
1
2
3

Sugammadex
(n = 66)

Neostigmine
(n = 67)

51
79
166
49

51
77
168
43

(16)
(16)
(9)
(74%)

(14)
(18)
(8)
(64%)

1 (2%)
65 (98%)

0
67 (100%)

15 (23%)
41 (62%)
10 (15%)

15 (22%)
47 (70%)
5 (7%)

from post-anaesthesia care unit admission to being

ready for discharge was similar in both groups
(Table 2).
994

Figure 2 Cumulative percentage of patients recovering

to a train-of-four (TOF) ratio of 0.9 over time for
sugammadex ( ) and neostigmine ( ).

Regarding safety, 65 66 patients (98%) experienced

at least one adverse event in the sugammadex group
compared to 65 67 (97%) for the neostigmine group;
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Geldner et al. | Sugammadex vs neostigmine at varying block

Anaesthesia 2012, 67, 991998

Table 2 Time (min) spent in the operating room and post-anaesthesia care unit in patients given either sugammadex
(deep neuromuscular blockade) or neostigmine (moderate neuromuscular blockade). Values are mean (SD) or estimated
mean treatment difference, sugammadex minus neostigmine (95% CI).

Operating room admission

to operating room discharge ready
Study drug administration to
tracheal extubation
Study drug administration to
operating room discharge ready
Post-anaesthesia care unit admission
to post-anaesthesia care unit
discharge ready

Sugammadex
(n = 66)

Neostigmine
(n = 65)

Estimated mean
treatment difference

154 (46)

165 (55)

)10.5 ()23.8, 2.7)

14 (8)

21 (11)

)6.5 ()9.3, )3.7)

< 0.0001

15 (8)

21 (11)

)5.9 ()8.7, )3.1)

< 0.0001

20 (28)

25 (40)

)4.2 ()15.2, 6.8)

0.46

p value
0.12

Table 3 Adverse events occurring in > 10% of at least

one treatment group, dened by Medical Dictionary for
Regulatory Activities preferred term. Values are number
(proportion).

Any adverse event

Procedural pain
Nausea
Anaesthetic
complication
cardiac*
Vomiting
C-reactive protein
increased

Sugammadex
(n = 66)

Neostigmine
(n = 67)

65
60
16
1

65
60
12
9

(98%)
(91%)
(24%)
(2%)

8 (12%)
8 (12%)

(97%)
(90%)
(18%)
(13%)

7 (10%)
6 (9%)

*All anaesthetic complication cardiac AEs were instances of

bradycardia.

adverse events (dened by the Medical Dictionary for

Regulatory Activities preferred term) occurring in
> 10% of at least one treatment group are presented
in Table 3. Serious adverse events were reported in ten
patients (8%), four in the sugammadex group and six
in the neostigmine group. Seven patients (11%) in the
sugammadex group and 16 (24%) in the neostigmine
plus atropine group had adverse events that were
considered, in the opinion of the blinded safety
assessor, to be at least possibly drug-related. Only
one serious adverse event was considered to be possibly
related to the study drug, a case of postoperative upper
abdominal pain after neostigmine. There was no
difference in blood pressure between the two groups;
however, heart rate was generally lower in the
neostigmine group compared with the sugammadex
Anaesthesia 2012 The Association of Anaesthetists of Great Britain and Ireland

Figure 3 Mean heart rate values by treatment group for

sugammadex (pale grey/squares) and neostigmine (dark
grey/circles). Error bars represent 2 SEM. *p = 0.0002
at 5 min, p < 0.0001 at 10 min, and p = 0.0001 at
30 min. NBD, neuromuscular blocking drug.
group (Fig. 3). Abnormally low heart rate values that
were considered to be clinically relevant by the
investigators were reported for ve patients in the
neostigmine group. Residual neuromuscular blockade
was not observed in any patients, and no patients
experienced a recurrence of neuromuscular blockade
based on neuromuscular monitoring. There was, however, a suggestion of clinical evidence of recurrence of
neuromuscular blockade in one patient, for whom
moderate dyspnoea was reported; this began 30 min
after sugammadex and lasted 45 min.
Overall, nine patients experienced PONV within
24 h of the procedure in the sugammadex group and
eight in the neostigmine group. In both groups, there
was a good relationship between increasing number of
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Geldner et al. | Sugammadex vs neostigmine at varying block

Table 4 Relationship between number of risk factors for postoperative nausea and vomiting (PONV) and number of
patients who experienced PONV within 24 h in patients given sugammadex or neostigmine. Values are number
(proportion).
Sugammadex
(n = 66)

Neostigmine
(n = 67)

Number of PONV
risk factors

Patients with
risk factors

Patients with
PONV

Patients with
risk factors

Patients with
PONV

0
1
2
3
4

1
7
22
30
6

0
0
0
4 (13%)
5 (83%)

0
15
22
25
5

0
0
0
4 (16%)
4 (80%)

(2%)
(11%)
(33%)
(45%)
(9%)

risk factors and increasing incidence of PONV

(Table 4).

Discussion
This is the rst randomised controlled study to compare
recovery time directly following sugammadex given at a
deep level of neuromuscular blockade with that following neostigmine given at a moderate level of blockade.
Despite the differences in the targeted level of neuromuscular blockade at the time of administration,
recovery was both statistically and clinically signicantly
quicker following sugammadex.
These results could be of particular signicance for
certain types of surgery, such as laparoscopic procedures, where a deep level of neuromuscular blockade
may permit improved surgical access and an enhanced
visual eld. Neostigmine is generally only considered to
be effective for reversal of neuromuscular blockade if
there has been some degree of spontaneous recovery,
something that may lead the anaesthetist to provide
less optimal conditions towards the end of surgery
because of the risk of residual blockade in the recovery
room [3, 9]. In contrast, our study has shown that the
use of sugammadex may allow anaesthetists to maintain a deep level of neuromuscular blockade towards
the end of surgery, without risking incomplete recovery
or other complications. The improved surgical eld of
view which may result from deep blockade might
permit the use of a lower pressure to create the
pneumoperitoneum, and this may in turn have additional benets such as reducing pain after laparoscopic
cholecystectomy [10].
Despite these benets, we were unable to show a
difference in the overall length of time spent by patients
996

(22%)
(33%)
(37%)
(7%)

from each group in the operating room and postanaesthesia care unit. Reduced time from study drug
administration to tracheal extubation did not translate
into more rapid discharge, which may have been due to
other factors such as pain management. If the depth of
neuromuscular blockade at the time of reversal of
neuromuscular blockade had been equivalent for both
drugs, greater differences between the groups may have
been observed. Therefore, to adjust for the depth of
neuromuscular blockade and to consider the numerous
other factors that may contribute to the duration of time
in the operating room and post-anaesthesia care unit,
further investigation is required.
Treatment with sugammadex was generally well
tolerated, and the overall number of adverse events was
comparable with that in the neostigmine group. However, the neostigmine group reported a greater number
of adverse events considered by the blinded safety
assessor to be related to the study drug, most
commonly bradycardia, which is well recognised as a
potential side effect of neostigmine [11, 12]. To combat
such side effects, anticholinergic drugs such as atropine
and glycopyrronium are frequently co-administered,
although these drugs may in turn lead to adverse events
of their own, including tachycardia, decreased secretions and blurred vision [13]. Thus, there is reluctance,
particularly in central Europe, to administer acetylcholinesterase inhibitors for the reversal of neuromuscular
blockade [14], with one survey suggesting that only
18% of European anaesthetists routinely use pharmacological reversal of neuromuscular blockade [15].
Sugammadex has a novel mechanism of action for the
reversal of neuromuscular blockade and acts to encapsulate the neuromuscular blocking agent, which is then
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Geldner et al. | Sugammadex vs neostigmine at varying block

unavailable to bind to the acetylcholine receptor at the

neuromuscular junction; this is not associated with
cholinergic effects [16, 17].
Previous studies have suggested that neostigmine
may be associated with PONV, particularly at doses over
2.5 mg [18], although there is currently insufcient
evidence to prove a clinically important increased risk
[19]. In our study, a greater number of risk factors
corresponded to an increased occurrence of PONV, thus
providing further validation of the predictive models
developed by Apfel et al. [7, 8]. The overall number of
PONV cases was similar between the two groups;
however, the small number of cases observed overall
makes it difcult to draw conclusions on these data.
To conclude, in patients undergoing laparoscopic
surgery under propofol anaesthesia, neuromuscular
blockade reversal with sugammadex administered at a
post-tetanic count of 12 (deep neuromuscular blockade) after rocuronium was well tolerated and resulted in
faster recovery of the TOF ratio to 0.9 compared with
neostigmine administered at reappearance of T2 (moderate neuromuscular blockade) (p < 0.0001). Sugammadex may therefore allow for rapid reversal of deep
neuromuscular blockade at the end of surgery without a
delay in recovery.

Acknowledgements
The authors thank all other investigators involved in this
study, including Professor Rainer Hofmockel (Klinik
und Poliklinik fur Anasthesiologie und Intensivtherapie,
Rostock, Germany), Dr Iain Moppett (Queens Medical
Centre, Nottingham, UK), Professor Yuri Polushin
(Military Medical Academy of S.M. Kirov, St. Petersburg, Russia), and all their colleagues, for their help in
the enrolment of patients and conduct of the study. The
clinical research scientist responsible for the study was
Martine E. Prins, MSc (formerly of MSD).
The study sponsor, MSD, was involved in both the
study design and analysis of the data. The overall design
and conduct of the study, as well as nal analysis of the
study data and opinions, conclusions and interpretation
of the data, are the responsibility of the authors. Medical
writing assistance was provided by Neil Venn, PhD, of
Prime Medica Ltd (Knutsford, UK); this assistance was
also funded by Merck Sharp and Dohme Corp., a
subsidiary of Merck & Co., Inc., Whitehouse Station, NJ.
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Anaesthesia 2012, 67, 991998

The study sponsor was allowed to review the manuscript

before submission, but nal decisions on content
remained the responsibility of the authors and all
authors approved the nal text of the manuscript before
submission.
Gotz Geldner has acted as a scientic advisor to
MSD (formerly Organon) and GlaxoSmithKline, has
delivered lectures for and received research funding
from both companies. Henk Rietbergen is an employee
of MSD. The other authors declare no competing
interests.

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