Clinical trial NCT03034577
Conditions: Laparoscopy Anesthesia Recovery Period
Sponsor: University of Melbourne
Start date: 2017-06-16; Completion date: 2019-04-01
Enrollment: 350 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Trial summary: deep neuromuscular block is proposed as a technique to improve operative conditions for laparoscopy. Early clinical data would suggest that there may also be patient benefits beyond the operative period related to lower intra-abdominal pressure, and improved surgical exposure. In order to safely conduct deep neuromuscular blockade, it is essential to use Sugammadex to reverse the neuromuscular block. Conventional practice is to provide moderate neuromuscular block and reverse with neostigmine. It is not possible to safely reverse deep neuromuscular block using neostogmine, as the majority of block must have worn off for neostigmine to be effective. in order to identify whether deep neuromuscular block improves quality of recovery after surgery, the investigators will conduct a randomised trial of deep versus moderate neuromuscular block, whilst minimising variance in other anaesthetic techniques and drugs used. the outcome measured will be the post-operative quality of recovery over multiple time periods using the Postoperative Quality of Recovery Scale (PostopQRS). 350 patients will be enrolled over 4 centres.

Detailed description:
Objectives

1\. To identify whether the rate/quality of recovery is affected by deep neuromuscular block (DNB) and reversal with sugammadex versus light/moderate neuromuscular block reversed with neostigmine and couple with desflurane or sevoflurane in patients undergoing operative gynecological or abdominal laparoscopic surgery of at least 1-hour duration.

Hypothesis

1\. The technique of deep neuromuscular block and reversal with sugammadex will result in improved quality of recovery, including cognition, compared to the current standard of care technique using light/moderate neuromuscular block reversed with neostigmine in patients undergoing operative gynecological or abdominal laparoscopic surgery of at least 1-hour duration.

Background:

Importance and assessment of quality of recovery

Recovery following general anesthesia is a complex issue confounded by the type of surgery, inflammation, different anesthetic drugs and techniques, patient co-morbidities, and differing patient and clinician perceptions of what constitutes good recovery.

Recovery is not a single entity but rather covers many aspects or domains such as physiological recovery, pain and nausea, emotion and mood, return to normal life or work activities, and cognitive function. It is an entity that is difficult to quantify, which then makes it difficult to study in a systematic manner. For anesthesiologists, poor recovery is often relayed by the surgeon days or weeks after the event, and it is usually categorized as an adverse outcome.

Research tools such as the Aldrete or the QoR scales, focus on early physiological recovery, or the immediate perioperative period. These recovery scores are not sensitive enough to measure the rate of recovery (change over time), and have not been designed for repeated measures. They are also inadequate to identify poor cognitive recovery.

In 2007, an international group of anesthesiologists and neuropsychologists formed an advisory board to create a new quality of recovery scale. The aim was to produce a tool that was simple to perform, but sensitive enough to detect change in multiple domains of recovery over time. The initial validation experiment included over 700 patients, and this work has been published in Anesthesiology. It is called the Postoperative Quality Recovery Scale (PostopQRS). Six domains of recovery are identified: physiological, nociceptive (pain and nausea) emotive (anxiety and depression), functional recovery (return of activities of daily living), cognitive recovery, and an overall patient perspective domain including satisfaction. The scale is completed prior to surgery to provide baseline values, and then repeated at user-defined intervals. From some of the subsequent discriminant validation studies, time points have included early and late measures such as 15 minutes, 40 minutes, 1 and 3 days, and 3 months after the completion of anesthesia (typically defined as after the last surgical stimulation). Recovery is broadly defined as return to baseline values or better, except for the cognitive domain where a tolerance factor is included to allow for normal performance variability, such that patients are allowed to perform a little worse than baseline as still be scored as recovered. Because repeated tests tend to have a learning effect, the cognitive domain uses parallel forms, and only a small learning has been shown.

One of the most important benefits of the PostopQRS scale is that it enables recovery to be quantified and measured. This makes it possible to compare different interventions with the express purpose of developing clinical interventions to improve quality of recovery. The PostopQRS offers a tool to provide the recovery process to be examined. There are no other tools in existence that provide a comprehensive, sensitive assessment of the multiple aspects or domains of recovery, and is yet relatively simple to perform. Validation studies have been performed and show good discriminative ability (5-8). Ease of use is facilitated by using a web based data entry system and the ability to use the telephone to conduct surveys after discharge form hospital. Telephone survey has been shown to be equivalent to face to face interviews using the PostopQRS. Further, the PostopQRS allows users to drill down to identify which recovery domain is affected for individuals in real time as well as for group audit.

Quality of recovery after operative laparoscopy

The majority of the literature compares different operative techniques with outcome measures aimed at specific complications or length of stay. Few studies include quality of recovery or quality of life measures as secondary endpoints. However, for potential benefits relating to the use of sugammadex, there are a few studies primarily centered around deep neuromuscular block (DNB) facilitating low intraabdominal inflation pressures. Most outcomes relate to operative conditions with little data on patient centered outcomes especially after discharge. The inclusion of sugammadex is to permit the use of DNB, and most comparative groups (of moderate block) are reversed with neostigmine.

It has been shown that more patients can be operated on with low intraabdominal pressure with DNB, and that operative conditions are rated as better in more patients with DNB, though it is not absolute and there are frequent crossovers. That is, there are patients with moderate block and low pressure, and equally patients with DNB requiring high inflation pressures. The very few data on patient centered outcomes show reduced pain and nausea after DNB, but lack of evidence of benefit for other recovery outcomes. This paucity of data has been stressed by review articles and editorials that DNB is associated with a modest effect on improving operating conditions but very little data to identify recovery benefits.

Sugammadex is an effective drug to reduce deep neuromuscular blockade

There is no clinical question that sugammadex is highly effective in reversing neuromuscular blockade with rocuronium or vecuronium. This has been the subject of a Cochrane review which included 18 randomized trials, showing that sugammadex can reverse blockade with rocuronium or vecuronium independent on the depth of block, and superiority to neostigmine. This aspect of sugammadex does not require further study. This translates to a low incidence of residual blockade in the PACU compared to neostigmine reversal. The "safety" benefit to using sugammadex has been proven, but this does not necessarily translate into better outcomes. Sugammadex, however, is an enabling drug to facilitate deep neuromuscular blockade, allowing the anesthesiologist to continue that block until the end of surgery and reliably reverse the block. This is just not possible with neostigmine reversal, as one must wait until a train of four count of at least 2 twitches (or TOF ratio \> 0.7) to safely reverse the block with neostigmine.

Sugammadex is not a single intervention

The role of sugammadex as a single intervention can only be applied when reversing neuromuscular block, when the block is moderate and a TOF 0.7 is achieved, with the outcome restricted to reversal of blockade.

When sugammadex is used as a tool to facilitate deep muscular block, the intervention is principally the DNB rather than sugammadex. In any randomized trial comparing sugammadex with neostigmine for reversal of DNB, the extra time that anesthesia is continued in the neostigmine group will be a confounder on post-operative outcomes. In a study comparing sugammadex vs. neostigmine to reverse DNB, the anesthetic time in the neostigmine group was almost double that of the sugammadex group (47 vs 95 min). This markedly increased anesthetic duration was due to the time taken for the TOF ratio to exceed 0.9 and facilitate safe extubation. It is therefore not possible to examine the issue of deep neuromuscular block and unbundle sugammadex from the anesthetic technique required.

Outcomes and confounders when assessing post-operative quality of recovery There are a few data assessing the impact of anesthetic drugs rather than surgical techniques or different operations on the post-operative quality recovery. It is very likely that different anesthetic drugs may independently contribute to changes in post-operative quality of recovery, over and above the use of deep neuromuscular block for laparoscopic surgery.

The two most commonly used anesthetic drugs are propofol and sevoflurane. Both are relatively short acting drugs, but have a wide variation of offset, particularly with more prolonged anesthesia, and patient factors such as morbid obesity. Desflurane is a volatile agent which is very short acting, and more importantly has highly predictable offset, which is independent of patient factors such as obesity or of operation duration. In patients receiving moderate neuromuscular block and reversal with neostigmine, the use of desflurane lead to earlier response to command and return of airway reflexed compared to sevoflurane.

The investigators research group is currently conducting research into different anesthetic techniques. Previously, the investigators studied effect of desflurane vs. propofol in patients undergoing cardiac surgery, and showed less cognitive dysfunction one week after surgery but not at three months after surgery with desflurane. The investigators have recently concluded but not published a pilot study investigating propofol sedation vs. desflurane general anesthesia to supplement spinal anesthesia for total hip replacement. The participant numbers are too small for meaningful statistical analysis, but there is a trend towards improved recovery and better cognitive recovery in the desflurane group (absolute difference 15% and OR 2.3). What is interesting, though, is that the early differences were negligible, and the trend occurred at 1 month and 3 months after surgery.

In this study, the investigators wish to primarily investigate the effect of the role of DNB, and to reduce the potential for confounding from different anesthetic techniques, we will standardize the anesthetic to use the shortest acting anesthetic bundle, and use desflurane coupled with short acting opiates and multimodal analgesia in patients undergoing operative gynecological or abdominal laparoscopic surgery of at least 1-hour duration.

Clinical significance

Quality of recovery is an emerging field within anesthesia of great importance. Although large outcome studies are very important in anesthesia, there is a changing focus from "mortality and morbidity studies", to quality of recovery. The reason is that the frequency of mortality is now very low with the result that few interventions will further reduce mortality and in any event very large numbers will be required to demonstrate any improvements in surgery and anesthesia with mortality as an outcome. However early data on the PostopQRS as well as clinical reports indicate that the quality of recovery is often poor in many patients, and yet these are not identified by the treating anesthesiologist. There are implications for the individual patient, for the practice of anesthesia, and for the community (such as safe return to work or to driving).

If providing deep neuromuscular block does lead to improved quality outcomes, then it is essential to use sugammadex to reverse the block. There may be benefits (such as cognitive recovery) that may be worsened by drugs such as neostigmine and avoidance of neostigmine may be a mechanism of improving recovery. The coupling of drugs with similar offset times may further lead to improved quality of recovery.

Arms: arm 1: Moderate Neuromuscular block: participants will receive moderate neuromuscular blockade with rocuronium aiming for TOF 0-2 twitches, with neostigmine reversal when the TOF at least 3 twitches. The depth of neuromuscular block may be reduced after completion of the majority of surgical excision to TOF 3 or more

Neostigmine arm 2: Deep Neuromuscular block: participants will receive DNB aiming for a post tetanic count of 1-2, which will be maintained until removal of the laparoscopic ports, with reversal using sugammadex
Interventions: intervention 1: Sugammadex intervention 2: Neostigmine
Intervention descriptions: intervention 1: Reversal of neuromuscular block Sugammadex dosage will be adjusted to body weight and PTC/TOF count at the time of reversal, and not administered until PTC at least 1. Dosage will be 4mg/kg if TOF = 0 and PTC ≥ 1; and 2 mg/kg if TOF ≥1. intervention 2: Neostigmine 50 micrograms/kg coupled with atropine 20 micrograms/kg or glycopyrrolate 5 micrograms/kg, to a maximum dose of neostigmine of 5.0 mg. The neostigmine should not be administered until the TOF has at least 3 twitches present.

Protocol documents:
Prot_000.pdf: 
       Protocol  Version 1  
1 
24 November 2016  
 
 
 
 
 
Prof Colin Royse 
 
Study Title: 
  
A randomized trial of deep neuromuscular blockade reversed with sugammadex 
versus moderate neuromuscular block reversed with neostigmine, on postoperative 
quality of recovery 
Institution Name 
 
The University of Melbourne 
Investigator Contact 
Information: 
­ Full address  
­ Phone No. 
­ Fax  No. 
­ e-mail address 
Professor Colin Royse 
Department of Surgery 
LEVEL 6 Clinical Medical Research Building, The Royal Melbourne Hospital 
Post: PO Box 2135, RM 
H, Victoria 3050 
P: +61383445673 
M: +61408467548 
F: +61386794445 
E: colin.royse@unimelb.edu.au 
 
 
 


       Protocol  Version 1  
2 
24 November 2016  
 
Section #2- Core Protocol 
2.1 Objectives & 
Hypotheses  
 
 
 
 
Objectives 
 
1.  To identify whether the rate/quality of recovery is affected by deep neuromuscular 
block (DNB) and  reversal with sugammadex versus light/moderate neuromuscular 
block reversed with neostigmine in patients undergoing operative gynecological or 
abdominal laparoscopic surgery of at least 1-hour duration. 
 
 
Hypothesis 
 
1.  The technique of deep neuromuscular block and  reversal with sugammadex will 
result in improved quality of recovery, including cognition, compared to the current 
standard of care technique using light/moderate neuromuscular block reversed with 
neostigmine in patients undergoing operative gynecological or abdominal 
laparoscopic surgery of at least 1-hour duration. 
 
 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Importance and assessment of quality of recovery 
 
Recovery following general anesthesia is a complex issue confounded by the type of 
surgery, inflammation, different anesthetic drugs and techniques, patient co-
morbidities, and differing patient and clinician perceptions of what constitutes good 
recovery. 
 
Recovery is not a single entity but rather covers many aspects or domains such as 
physiological recovery, pain and nausea, emotion and mood, return to normal life or 
work activities, and cognitive function.  It is an entity that is difficult to quantify, which 
then makes it difficult to study in a systematic manner. For anesthesiologists, poor 
recovery is often relayed by the surgeon days or weeks after the event, and it is 
usually categorized as an adverse outcome. 
 
Research tools such as the Aldrete (1)  or the QoR (2, 3)   scales, focus on early 
physiological recovery,  or the immediate perioperative period.   These recovery 
scores are not sensitive enough to measure the rate of recovery (change over time), 
and have not been designed for repeated measures. They are also inadequate to 
identify poor cognitive recovery. 
 
In 2007, an international group of anesthesiologists and neuropsychologists formed 
an advisory board to create a new quality of recovery scale. The aim was to produce 
a tool that was simple to perform, but sensitive enough to detect change in multiple 
domains of recovery over time. The initial validation experiment included over 700 
patients, and this work has been published in Anesthesiology. It is called the 
Postoperative Quality Recovery Scale (PostopQRS)(4).   Six domains of recovery 
are identified: physiological, nociceptive (pain and nausea) emotive (anxiety and 
depression), functional recovery (return of activities of daily living), cognitive 
recovery, and an overall patient perspective domain including satisfaction. The scale 
is completed prior to surgery to provide baseline values, and then repeated at user-
defined intervals. From some of the subsequent discriminant validation studies, time 
points have included early and late measures such as 15 minutes, 40 minutes, 1 and 
3 days, and 3 months after the completion of anesthesia (typically defined as after 
the last surgical stimulation). Recovery is broadly defined as return to baseline 
values or better, except for the cognitive domain where a tolerance factor is included 
to allow for normal performance variability, such that patients are allowed to perform 


       Protocol  Version 1  
3 
24 November 2016  
a little worse than baseline as still be scored as recovered (5).  Because repeated 
tests tend to have a learning effect, the cognitive domain uses parallel forms, and 
only a small learning has been shown (5).  
 
One of the most important benefits of the PostopQRS scale is that it enables 
recovery to be quantified and measured. This makes it possible to compare different 
interventions with the express purpose of developing clinical interventions to improve 
quality of recovery. The PostopQRS offers a tool to provide the recovery process to 
be examined. There are no other tools in existence that provide a comprehensive, 
sensitive assessment of the multiple aspects or domains of recovery, and is yet 
relatively simple to perform. Validation studies have been performed and show good 
discriminative ability (5-8). Ease of use is facilitated by using a web based data entry 
system and the ability to use the telephone to conduct surveys after discharge form 
hospital. Telephone survey has been shown to be equivalent to face to face 
interviews using the PostopQRS (5). Further, the PostopQRS allows users to drill 
down to identify which recovery domain is affected for individuals in real time as well 
as for group audit. 
 
Quality of recovery after operative laparoscopy 
 
The majority of the literature compares different operative techniques with outcome 
measures aimed at specific complications or length of stay. Few studies include 
quality of recovery or quality of life measures as secondary endpoints (9-12). 
However, for potential benefits relating to the use of sugammadex, there are a few 
studies primarily centered around deep neuromuscular block (DNB) facilitating low 
intraabdominal inflation pressures. Most outcomes relate to operative conditions with 
little data on patient centered outcomes especially after discharge.  The inclusion of 
sugammadex is to permit the use of DNB, and most comparative groups (of 
moderate block) are reversed with neostigmine.  
 
It has been shown that more patients can be operated on with low intraabdominal 
pressure with DNB, and that operative conditions are rated as better in more patients 
with DNB (13, 14), though it is not absolute and there are frequent crossovers. That 
is, there are patients with moderate block and low pressure, and equally patients 
with DNB requiring high inflation pressures. The very few data on patient centered 
outcomes show reduced pain and nausea after DNB (13, 15-17), but lack of 
evidence of benefit for other recovery outcomes. This paucity of data has been 
stressed by review articles and editorials that DNB is associated with a modest effect 
on improving operating conditions but very little data to identify recovery benefits (13, 
18) 
 
Sugammadex is an effective drug to reduce deep neuromuscular blockade 
 
There is no clinical question that sugammadex is highly effective in reversing 
neuromuscular blockade with rocuronium or vecuronium. This has been the subject 
of a Cochrane review which included 18 randomized trials, showing that 
sugammadex can reverse blockade with rocuronium or vecuronium independent on 
the depth of block, and superiority to neostigmine (19). This aspect of sugammadex 
does not require further study. This translates to a low incidence of residual blockade 
in the PACU compared to neostigmine reversal. The "safety" benefit to using 
sugammadex has been proven, but this does not necessarily translate into better 
outcomes. Sugammadex, however, is an enabling drug to facilitate deep 
neuromuscular blockade, allowing the anesthesiologist to continue that block until 
the end of surgery and reliably reverse the block. This is just not possible with 
neostigmine reversal, as one must wait until a train of four count of at least 2 
twitches (or TOF ratio > 0.7) to safely reverse the block with neostigmine. 


       Protocol  Version 1  
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24 November 2016  
 
Sugammadex is not a single intervention 
 
The role of sugammadex as a single intervention can only be applied when reversing 
neuromuscular block, when the block is moderate and a TOF 0.7 is achieved, with 
the outcome restricted to reversal of blockade. 
 
When sugammadex is used as a tool to facilitate deep muscular block, the 
intervention is principally the DNB rather than sugammadex. In any randomized trial 
comparing sugammadex with neostigmine for reversal of DNB, the extra time that 
anesthesia is continued in the neostigmine group will be a confounder on post-
operative outcomes. In a study comparing sugammadex vs. neostigmine to reverse 
DNB, the anesthetic time in the neostigmine group was almost double that of the 
sugammadex group (47 vs 95 min) (20). This markedly increased anesthetic 
duration was due to the time taken for the TOF ratio to exceed 0.9 and facilitate safe 
extubation. It is therefore not possible to examine the issue of deep neuromuscular 
block and unbundle sugammadex from the anesthetic technique required. 
 
Outcomes and confounders when assessing post-operative quality of recovery
There are a few data assessing the impact of anesthetic drugs rather than surgical 
techniques or different operations on the post-operative quality recovery. It is very 
likely that different anesthetic drugs may independently contribute to changes in 
post-operative quality of recovery, over and above the use of deep neuromuscular 
block for laparoscopic surgery.   
 
The two most commonly used anesthetic drugs are propofol and sevoflurane. Both 
are relatively short acting drugs, but have a wide variation of offset, particularly with 
more prolonged anesthesia, and patient factors such as morbid obesity (21-23). 
Desflurane is a volatile agent which is very short acting, and more importantly has 
highly predictable offset, which is independent of patient factors such as obesity (21) 
or of operation duration. In patients receiving moderate neuromuscular block and 
reversal with neostigmine, the use of desflurane lead to earlier response to 
command and return of airway reflexed compared to sevoflurane (24). 
 
Our research group is currently conducting research into different anesthetic 
techniques. Previously, we studied effect of desflurane vs.  propofol in patients 
undergoing cardiac surgery, and showed less cognitive dysfunction one week after 
surgery but not at three months after surgery with desflurane (25). We have recently 
concluded but not published a pilot study investigating propofol sedation vs. 
desflurane general anesthesia to supplement spinal anesthesia for total hip 
replacement. The participant numbers are too small for meaningful statistical 
analysis, but there is a trend towards improved recovery and better cognitive 
recovery in the desflurane group (absolute difference 15% and OR 2.3). What is 
interesting, though, is that the early differences were negligible, and the trend 
occurred at 1 month and 3 months after surgery. 
 
The recovery graphs for the PostopQRS are shown below.  The Y axis is the 
proportion of patients recovered for each domain, and the X axis shown the time 
points where the PostopQRS was conducted.  
 
 
 


       Protocol  Version 1  
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24 November 2016  
 
 
 
 
Our data cannot explain why there were differences late rather than early. However, 
the cognitive domain is very sensitive to pain, analgesics and inflammation, and it is 
possible that modest but clinically important differences could be masked early after 
surgery by these factors, and only become evident after the inflammation and 
requirement for analgesia ceases. There were no intermediate time points between 3 
days and 1 month, so we cannot be sure when this possible effect is starting.  
 
We are conducting a blinded study for sevoflurane vs. desflurane for knee 
arthroscopy and measuring recovery using the PostopQRS. However, we performed 
a blinded interim analysis, which shows group separation of around 10% in recovery 
15 mins
40 mins
1 day
3 days
1 month
3 months
0
20
40
60
80
100
Post-operative time points
% of patients recovered
Cognitive recovery
Propofol
Desflurane
A
15 mins
40 mins
1 day
3 days
1 month
3 months
0
20
40
60
80
100
Post-operative time points
% of patients recovered
Physiological recovery
Propofol
Desflurane
C
15 mins
40 mins
1 day
3 days
1 month
3 months
0
20
40
60
80
100
Post-operative time points
% of patients recovered
Emotive recovery
Propofol
Desflurane
E
15 mins
40 mins
1 day
3 days
1 month
3 months
0
20
40
60
80
100
Post-operative time points
% of patients recovered
Overall recovery
Propofol
Desflurane
B
15 mins
40 mins
1 day
3 days
1 month
3 months
0
20
40
60
80
100
Post-operative time points
% of patients recovered
Nociceptive recovery
Propofol
Desflurane
D
15 mins
40 mins
1 day
3 days
1 month
3 months
0
20
40
60
80
100
Post-operative time points
% of patients recovered
ADL recovery
Propofol
Desflurane
F


       Protocol  Version 1  
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24 November 2016  
and cognitive domain at the 1-month time point, but not at earlier or later time points.  
The cognitive domain is shown below: 
 
 
Further, it is possible that other components of the anesthetic technique such as 
analgesia could also be a confounder in recovery. 
 
The importance of the anesthetic confounders, is that is not possible to unbundle 
sugammadex from the anesthetic and still provide deep block, due to the much 
longer anesthesia time if neostigmine is used.  
 
The concept of anesthetic bundles of technique 
 
This introduces the concept of bundling agents together which have similar offset 
properties, and comparing that to real-world practice of light/moderate block, reversal 
with neostigmine and typically using sevoflurane as the maintenance anesthetic. The 
group receiving short acting drugs should have much less variance between 
effective block reversal and emergence, whilst at the same time facilitate optimal 
operating conditions. The coupling of agents should provide the greatest group 
separation for the use of sugammadex and potentially for postoperative quality 
outcomes. 
 
In this study, we wish to primarily investigate the effect of the role of DNB, and to 
reduce the potential for confounding from different anesthetic techniques, we will 
standardize the anesthetic to use the shortest acting anesthetic bundle, and use 
desflurane coupled with short acting opiates and multimodal analgesia in patients 
undergoing operative gynecological or abdominal laparoscopic surgery of at least 1-
hour duration.  
 
The research team 
The team will be managed by Prof Colin Royse at the University of Melbourne. Colin 
is one of the founders of the PostopQRS and is the co-director of the group. We aim 
to recruit centers with high volume of operative gynecological or abdominal 
laparoscopic surgery. The University of Melbourne department is co-located with the 
Royal Melbourne Hospital and the Royal Women’s Hospital, and connected to our 
specialist cancer hospital the Peter MacCallum Cancer Center. We also have access 
to a private hospital (Northpark Private Hospital) which has a high volume of 
gynecological surgery. These centers will be the initial target hospitals with potential 
to expand the number of hospitals once the trial is underway. The team statistician is 


       Protocol  Version 1  
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24 November 2016  
Dr. Sandy Clarke, Statistical Consulting Centre, Department of Mathematics, The 
University of Melbourne. 
 
Clinical significance 
 
Quality of recovery is an emerging field within anesthesia of great importance.  
Although large outcome studies are very important in anesthesia, there is a changing 
focus from “mortality and morbidity studies”, to quality of recovery. The reason is that 
the frequency of mortality is now very low with the result that few interventions will 
further reduce mortality and in any event very large numbers will be required to 
demonstrate any improvements in surgery and anesthesia with mortality as an 
outcome. However early data on the PostopQRS as well as clinical reports indicate 
that the quality of recovery is often poor in many patients, and yet these are not 
identified by the treating anesthesiologist.  There are implications for the individual 
patient, for the practice of anesthesia, and for the community (such as safe return to 
work or to driving).  
 
If providing deep neuromuscular block does lead to improved quality outcomes, then 
it is essential to use sugammadex to reverse the block. There may be benefits (such 
as cognitive recovery) that may be worsened by drugs such as neostigmine and 
avoidance of neostigmine may be a mechanism of improving recovery. The coupling 
of drugs with similar offset times may further lead to improved quality of recovery. 
 
2.3 Study Design 
 
Study design 
 
Parallel randomized trial with allocation ration 1:1. The trial will be registered prior to 
commencement and will conform too CONSORT guidelines. 
 
Study environment 
 
The study will be conducted in a secondary or tertiary hospitals, which have an active 
laparoscopic surgery unit for gynecology or abdominal surgery.  It is anticipated that a 
24-month study period will be required.  The combined institutions conduct more than 
40 elective operative laparoscopies per week, making an average of 8 patients per 
week recruitment very feasible to achieve.  Additional study sites will be added to 
increase recruitment if required.  
 
Eligibility criteria 
 
Inclusion: 
1. Adult participants undergoing operative gynecological or abdominal surgery 
under general anesthesia of at least 1 hour duration 
 
Exclusion: 
1. Participants, who are not fluent in English will be excluded, as they may be 
unable to answer the recovery questionnaire adequately.  
2. Participants undergoing diagnostic laparoscopy only 
3. Participants <18 years of age 
4. Current pregnancy 
5. Known allergy to rocuronium, neostigmine or sugammadex, or desflurane  
 


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2.4 Study Flowchart 
 
2.5 Study 
Procedures 
Interventions 
 
Common management will include the following 
 
1. Pre-medication other than oral analgesic (such as paracetamol) will not be used. 
 
2.  Induction will be with intravenous propofol, including co-induction consisting of 
fentanyl 0.5-3.0 mcg/kg, or equivalent short acting opiate including remifentanil. 
 
3. Analgesia will consist of multimodal analgesia as determined by the 
anesthesiologist to treat the degree of pain, but in principle to avoid long acting 
opiates, e.g. use intraoperative short acting opiates, 1 g acetaminophen qid, 
NSAID’s including Cox II inhibitors (such as paracoxib 40mg i.v.), or oxycontin 10-
20mg 6 hourly.  
 
4. Dual antiemetic therapy as per hospital guidelines 
 
5. The maintenance anesthetic will be desflurane, and will be titrated to effect by the 
attending anesthesiologist 
 
6. Rocuronium administration: for moderate neuromuscular block an initial dose of 
0.6 mg/kg, with repeat doses of 0.15mg/kg given if the TOF >2 twitches. After 
completion of the majority of surgical resection, the level of block may be reduced to 
at least 3 twitches in preparation for  the end of surgery. 
 
 For DNB, the initial dose will be 1.2 mg/kg and repeat doses of 0.15 mg/kg until PTC 
≤ 2. TOF counts may be checked as frequently as every 15 seconds, but the PTC 
count interval must be at least 2 minutes (26).  
 
7.  If vecuronium ( a similar steroidal muscle relaxant) is used instead 
of  Rocuronium, then the dose is reduced to 10% of  the dose of rocuronium, and 
titrated to achieve the same TOF endpoints.  
 
8. Reversal of neuromuscular block 
 
a. Neostigmine 50 micrograms/kg coupled with atropine 20 micrograms/kg or 
glycopyrrolate 5 micrograms/kg, to a maximum dose of neostigmine of 5.0 mg. The 
neostigmine should not be administered until the TOF has at least 3 twitches 
present. 
 
 
b. Sugammadex dosage will be adjusted to body weight and PTC/TOF count 
at the time of reversal, and not administered until PTC at least 1. Dosage will be 
4mg/kg if TOF = 0 and PTC ≥ 1; and 2 mg/kg if TOF ≥1. 
 
9. Extubation for all groups will occur when the TOF has 4 twitches with no visible 
fade, (or a TOF ratio > 0.7 for institutions using a TOF ratio measurement device) 
adequate respiration and degree of alertness as determined by the anesthesiologist 


       Protocol  Version 1  
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24 November 2016  
as safe for extubation. Patients  should not leave the operation room until  TOF has 
4 twitches with no visible fade, or for institutions using a TOF ratio measurement 
device, a TOF ratio > 0.9. 
 
 
Intervention –groups 
 
 
1. ModNB  - participants will receive moderate neuromuscular blockade with 
rocuronium aiming for TOF  0-2 twitches, with neostigmine reversal when the TOF at 
least 3 twitches. After completion of the majority of surgical resection, the levl of 
block may be reduced to at least 3 twitches in preparation for  the end of surgery. 
 
 
2. DNB– participants will receive DNB aiming for a post tetanic count of 1-2, which 
will be maintained until removal of the laparoscopic ports, with reversal using 
sugammadex.  
 
 
Study assessments protocol 
 
Quality of recovery will be assessed using the Postoperative Quality of Recovery 
Scale (PostopQRS) see www.postopqrs.com. The survey takes around 5-6 minutes 
on each occasion to administer and is conducted either face-to-face whilst the 
participant is in hospital or via the telephone when discharged. Five recovery 
domains are assessed (physiological, nociceptive, emotive, function (ADL) and 
cognitive, and an additional overall patient perspective domain is recorded including 
satisfaction. 
 
The scale will be conducted prior to surgery (baseline) and at 15 mins, 40 mins, 1 
and 3 days, 1 and 2 weeks, 1 and 3 months after surgery to track recovery from the 
immediate to long-term. 
 
Outcome measurements  
 
Primary outcome 
 
The most sensitive recovery domain of the Postoperative Quality of Recovery Scale 
to the effects of short acting drugs and avoidance of neostigmine is cognition. The 
primary outcome will be the cognitive domain at 1 week after surgery, when it is 
expected that most of the acute inflammation will have resolved, and analgesia 
requirements minimal.   
 
Secondary outcomes 
1. Recovery for all domains and within domains at the other time points of 
measurement (15 minutes, 40 minutes 1 day, 3 days, 1 and 2 weeks, and 3 months 
following cessation of anesthesia). The domains of recovery are physiological, 
nociceptive, emotive activities of daily living, cognitive and overall patient 
perspective. 
 
2. Compliance with protocol to ensure deep block or light/moderate block, and 
correctly assigned anesthetic.  
 
3. Anesthesia, surgical (first incision to last stitch), operating room, and PACU times, 
and hospital length of stay 
 


       Protocol  Version 1  
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4.  Incidence of persistent neuromuscular block (TOF < 4 twitches or visible fade, or 
TOF ratio < 0.9) upon arrival in the PACU. 
 
5. Surgical operating conditions measured by maximal inflation pressure required for 
surgery, and number of times that organ movement occurred (due to diaphragmatic 
movement or abdominal wall tone), and overall surgical satisfaction using a 1-5 
Likert scale (1 = very unacceptable, 2 = unacceptable, 3 = acceptable, 4 = good, 5 = 
excellent). 
 
Ethical issues 
 
This study will be reviewed by the Melbourne Health HREC. All patients will receive 
a written plain language statement and will provide informed written consent. 
 
Both  neuromuscular reversal drugs are commonly used in Australia. If the 
participating anesthesiologist believes that the anesthetic regimen is inappropriate, 
then the patient will not be recruited into the study. The concept of deep 
neuromuscular block is relatively new in laparoscopic surgery as it can only be safely 
performed if reversal can be reliably achieved in an acceptable time frame. 
Accordingly, the deep neuromuscular block group will receive sugammadex using 
dosage guidelines according to body weight and degree of neuromuscular block at 
the time of reversal.  Each PostopQRS measurement takes approximately 5-10 
minutes, and is not onerous or stressful to the patient. However, if the patient does 
not wish to participate further, then they may withdraw from the study.  
Measurements performed after discharge from hospital are conducted via telephone 
interviews and do not require the patient to return to the hospital or other location. 
The interviews are arranged between the researcher and patient at a time of mutual 
convenience. 
 
 
 
2.6 Study Duration 
Anticipated time-line 
 
The aim is to recruit an average of 4-6 patients per week (at least 4 hospitals to 
participate, with potential to add more hospitals).  That timeline for the study 
schedule is listed below, though could advance earlier if recruitment is faster than 
anticipated.  
 
Objective 
3 months  
3-12 months  
12 -21 months 
21-24 
months  
Ethics 
XXXXXXXX 
 
 
 
Recruit 40% 
 
XXXXXXXXX 
 
 
Recruit 100% 
 
                  
XXXXXXXXX 
 
Complete 3 
month follow 
up 
 
 
 
XXXX 
Analysis and 
manuscript 
 
 
 
 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
 
The team statistician is Dr. Sandy Clarke, Statistical Consulting Centre, Department 
of Mathematics, The University of Melbourne, who will oversee the statistical analysis.
 
Study size 
Sample size estimates are based on the primary outcome of cognitive recovery at 1 
week after surgery, and a clinically important difference in cognitive recovery at 1 week 


       Protocol  Version 1  
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24 November 2016  
after surgery of 15%. Estimates of cognitive recovery are based on prior PostopQRS 
research and using multiple ages and surgical cohorts. It is estimated that the cognitive 
recovery for this cohort and duration of surgery will be 85% if there is good recovery. 
Using a two tailed estimate and Chi-squared analysis, alpha of 0.05, and power of 
90%, with 1:1 allocation ratio; the sample size required to detect an absolute difference 
of 15% is 161 per group, which will be rounded up to a total sample size of 350  patients 
to account for potential non-completion of the study 
 
Statistical methods 
 
Variables of “recovery” are dichotomized to "recovered" or "not recovered" based on 
whether they have achieved baseline values or better at each of the time points when 
measurement is performed. A tolerance factor is included in the scoring of cognitive 
recovery to allow for performance variability (5). Statistical analysis for the primary 
outcome will be with the Chi-squared test. For the secondary outcomes of recovery 
over time, analysis will be performed using the a general linear mixed model to 
investigate group differences over time. Continuous data will be analyzed using 
independent samples t test, or RM ANOVA for repeated measurements. A P<0.05 will 
define statistical significance, and P<0.01 will define statistical significance for 
secondary endpoints to reduce risk of Type I error. Analysis is intention to treat. 
 
Randomization 
 
The randomization sequence will be produced using a computer generated 
randomization sequence, in unequal blocks and stratified for gynecological and 
abdominal surgery. Concealment will be by placing the card containing the allocation 
information in double opaque sealed envelopes, and concealment will be maintained 
until after recruitment and the patients is admitted to the operating theatre. The treating 
anesthesiologist will then open the envelopes to reveal the allocation. A non-
participant in any process of the study will perform preparation of the envelopes. A 
copy of the randomization sequence will be stored in a separate databank, which is 
password protected and not available to the investigators until the study is complete.  
 
Blinding 
Due to the nature of the drugs, it is not possible to blind the treating anesthesiologist 
to the allocation, but the patient and study investigators who collect the PostopQRS 
data will be blinded to allocation. 
 
 
2.9 Adverse 
Experience 
Reporting 
A data monitoring committee will be established and chaired by a senior academic 
who is not part of the clinical trial conduct. Adverse events will be reported to the 
HREC. 
2.10 References 
References  
 
1. 
Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg. 
1970;49(6):924-34. 
2. 
Myles PS, Reeves MD, Anderson H, Weeks AM. Measurement of quality of 
recovery in 5672 patients after anaesthesia and surgery. Anaesth Intensive Care. 
2000;28(3):276-80. 
3. 
Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability 
of a postoperative quality of recovery score: the QoR-40. Br J Anaesth. 2000;84(1):11-
5. 


       Protocol  Version 1  
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24 November 2016  
4. 
Royse CF, Newman S, Chung F, Stygall J, McKay RE, Boldt J, et al. 
Development and feasibility of a scale to assess postoperative recovery: the post-
operative quality recovery scale. Anesthesiology. 2010;113(4):892-905. 
5. 
Royse CF, Newman S, Williams Z, Wilkinson DJ. A human volunteer study to 
identify variability in performance in the cognitive domain of the postoperative quality 
of recovery scale. Anesthesiology. 2013;119(3):576-81. 
6. 
Newman S, Wilkinson DJ, Royse CF. Assessment of early cognitive recovery 
after surgery using the Post-operative Quality of Recovery Scale. Acta Anaesthesiol 
Scand. 2014;58(2):185-91. 
7. 
Royse CF, Williams Z, Ye G, Wilkinson D, De Steiger R, Richardson M, et al. 
Knee surgery recovery: Post-operative Quality of Recovery Scale comparison of age 
and complexity of surgery. Acta Anaesthesiol Scand. 2014;58(6):660-7. 
8. 
Royse CF, Williams Z, Purser S, Newman S. Recovery after nasal surgery vs. 
tonsillectomy: discriminant validation of the Postoperative Quality of Recovery Scale. 
Acta Anaesthesiol Scand. 2014;58(3):345-51. 
9. 
Abbas AE, Abd Ellatif ME, Noaman N, Negm A, El-Morsy G, Amin M, et al. 
Patient-perspective quality of life after laparoscopic and open hernia repair: a 
controlled randomized trial. Surg Endosc. 2012;26(9):2465-70. 
10. 
Abd Ellatif ME, Askar WA, Abbas AE, Noaman N, Negm A, El-Morsy G, et al. 
Quality-of-life measures after single-access versus conventional laparoscopic 
cholecystectomy: a prospective randomized study. Surg Endosc. 2013;27(6):1896-
906. 
11. 
Bansal VK, Misra MC, Babu D, Victor J, Kumar S, Sagar R, et al. A 
prospective, randomized comparison of long-term outcomes: chronic groin pain and 
quality of life following totally extraperitoneal (TEP) and transabdominal preperitoneal 
(TAPP) laparoscopic inguinal hernia repair. Surg Endosc. 2013;27(7):2373-82. 
12. 
Barkun JS, Wexler MJ, Hinchey EJ, Thibeault D, Meakins JL. Laparoscopic 
versus open inguinal herniorrhaphy: preliminary results of a randomized controlled 
trial. Surgery. 1995;118(4):703-9; discussion 9-10. 
13. 
Koo BW, Oh AY, Seo KS, Han JW, Han HS, Yoon YS. Randomized Clinical 
Trial of Moderate 
Versus 
Deep 
Neuromuscular 
Block for Low-Pressure 
Pneumoperitoneum During Laparoscopic Cholecystectomy. World J Surg. 2016. 
14. 
Staehr-Rye AK, Rasmussen LS, Rosenberg J, Juul P, Lindekaer AL, Riber C, 
et al. Surgical space conditions during low-pressure laparoscopic cholecystectomy 
with deep versus moderate neuromuscular blockade: a randomized clinical study. 
Anesth Analg. 2014;119(5):1084-92. 
15. 
Staehr-Rye AK, Rasmussen LS, Rosenberg J, Juul P, Gatke MR. Optimized 
surgical space during low-pressure laparoscopy with deep neuromuscular blockade. 
Dan Med J. 2013;60(2):A4579. 
16. 
Madsen MV, Istre O, Staehr-Rye AK, Springborg HH, Rosenberg J, Lund J, 
et al. Postoperative shoulder pain after laparoscopic hysterectomy with deep 
neuromuscular blockade and low-pressure pneumoperitoneum: A randomised 
controlled trial. Eur J Anaesthesiol. 2016;33(5):341-7. 
17. 
Kim MH, Lee KY, Lee KY, Min BS, Yoo YC. Maintaining Optimal Surgical 
Conditions With Low Insufflation Pressures is Possible With Deep Neuromuscular 
Blockade During Laparoscopic Colorectal Surgery: A Prospective, Randomized, 
Double-Blind, Parallel-Group Clinical Trial. Medicine (Baltimore). 2016;95(9):e2920. 
18. 
Kopman AF, Naguib M. Laparoscopic surgery and muscle relaxants: is deep 
block helpful? Anesth Analg. 2015;120(1):51-8. 
19. 
Abrishami A, Ho J, Wong J, Yin L, Chung F. Cochrane corner: sugammadex, 
a selective reversal medication for preventing postoperative residual neuromuscular 
blockade. Anesth Analg. 2010;110(4):1239. 
20. 
Carron M, Veronese S, Foletto M, Ori C. Sugammadex allows fast-track 
bariatric surgery. Obes Surg. 2013;23(10):1558-63. 
21. 
McKay RE, Malhotra A, Cakmakkaya OS, Hall KT, McKay WR, Apfel CC. 
Effect of increased body mass index and anaesthetic duration on recovery of 


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24 November 2016  
protective airway reflexes after sevoflurane vs desflurane. Br J Anaesth. 
2010;104(2):175-82. 
22. 
McKay RE, Bostrom A, Balea MC, McKay WR. Airway responses during 
desflurane versus sevoflurane administration via a laryngeal mask airway in smokers. 
Anesth Analg. 2006;103(5):1147-54. 
23. 
McKay RE, Large MJ, Balea MC, McKay WR. Airway reflexes return more 
rapidly after desflurane anesthesia than after sevoflurane anesthesia. Anesth Analg. 
2005;100(3):697-700, table of contents. 
24. 
McKay RE, Hall KT, Hills N. The Effect of Anesthetic Choice (Sevoflurane 
Versus Desflurane) and Neuromuscular Management on Speed of Airway Reflex 
Recovery. Anesth Analg. 2016;122(2):393-401. 
25. 
Royse CF, Andrews DT, Newman SN, Stygall J, Williams Z, Pang J, et al. The 
influence of propofol or desflurane on postoperative cognitive dysfunction in patients 
undergoing coronary artery bypass surgery. Anaesthesia. 2011;66(6):455-64. 
26. 
Groudine SB, Soto R, Lien C, Drover D, Roberts K. A randomized, dose-
finding, phase II study of the selective relaxant binding drug, Sugammadex, capable 
of safely reversing profound rocuronium-induced neuromuscular block. Anesth Analg. 
2007;104(3):555-62. 
 
2.12 Publication 
Plan 
 The main study will be aimed at Anesthesiology for the first submission. 
Presentations will be made at major international anesthesiology meetings 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan V1 17/06/2019 
Trial registration: NCT03034577 
1 
 
Statistical Analysis Plan 
A randomized trial of deep neuromuscular blockade reversed with 
sugammadex versus moderate neuromuscular block reversed with 
neostigmine, on postoperative quality of recovery 
 
Trial Registration Number:  NCT03034577 
Statistical Analysis Plan version 1 (17/06/2019) 
Protocol version 1 (24/11/2016) 
No history of Statistical Analysis Plan revision 
 
 
Dr Sandy Clarke:   
PhD, Senior Statistician, Department of Mathematics and Statistics, The University of Melbourne, Melbourne, Australia. 
Prof Colin Royse:  
MBBS, MD, FANZCA. Professor of Anesthesiology, Department of Surgery, The University of Melbourne, Melbourne Australia. 
Visiting Anesthesiologist, the Royal Melbourne Hospital, Melbourne Australia. Australian Director, Outcomes Research 
Consortium, Cleveland Clinic, Cleveland, USA.


Statistical Analysis Plan V1 17/06/2019 
Trial registration: NCT03034577 
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Signatures 
 
Statistical Analysis Plan written by: Prof Colin Royse 
Sign: ________________________________ 
 
Senior statistician: Dr Sandy Clarke 
 
Sign: ____________________________ 
 
Chief Investigator: Prof Colin Royse 
           
 
Sign: ________________________________ 
 
 
 
 
 
 
 
 


Statistical Analysis Plan V1 17/06/2019 
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Contents 
A randomized trial of deep neuromuscular blockade reversed with sugammadex versus moderate 
neuromuscular block reversed with neostigmine, on postoperative quality of recovery ............................ 1 
2. Introduction ............................................................................................................................................... 5 
2.1. Background and Rationale .................................................................................................................. 5 
2.2. Objectives and hypothesis .................................................................................................................. 8 
3. Study Methods ........................................................................................................................................... 9 
3.1. Trial Design ......................................................................................................................................... 9 
3.2. Randomization .................................................................................................................................... 9 
3.3. Sample Size ......................................................................................................................................... 9 
3.4. Framework ........................................................................................................................................ 10 
3.5. Statistical interim analyses and stopping guidance.......................................................................... 10 
3.6. Timing of final analyses – timeline of study ..................................................................................... 10 
3.7. Timing of outcome assessments ...................................................................................................... 10 
4. Statistical Principles ................................................................................................................................. 11 
4.1. Statistical significance ....................................................................................................................... 10 
4.2. Adjustments to the statistical significance ....................................................................................... 10 
4.3. Confidence intervals ......................................................................................................................... 11 
4.4. Adherence and Protocol deviations ................................................................................................. 11 
4.5. Definition of analysis populations .................................................................................................... 11 
5. Trial Populations ...................................................................................................................................... 12 


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5.1. Screening .......................................................................................................................................... 12 
5.2. Eligibility Criteria ............................................................................................................................... 12 
5.3. Recruitment ...................................................................................................................................... 12 
5.4. Withdrawal ....................................................................................................................................... 13 
5.5. Baseline Patient Characteristics ....................................................................................................... 13 
6. Analysis .................................................................................................................................................... 14 
6.1. Outcome definitions ......................................................................................................................... 14 
6.2. Analysis Methods .............................................................................................................................. 15 
6.3. Missing Data ..................................................................................................................................... 15 
6.4. Additional Analyses........................................................................................................................... 15 
6.5. Harms ................................................................................................................................................ 15 
6.6. Statistical Software ........................................................................................................................... 16 
6.7. References ........................................................................................................................................ 16 
 
 


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2. Introduction 
2.1. Background and Rationale  
Recovery following general anesthesia is a complex issue confounded by the type of surgery, 
inflammation, different anesthetic drugs and techniques, patient co-morbidities, and differing patient and 
clinician perceptions of what constitutes good recovery. 
 
Recovery is not a single entity but rather covers many aspects or domains such as physiological 
recovery, pain and nausea, emotion and mood, return to normal life or work activities, and cognitive 
function.  It is an entity that is difficult to quantify, which then makes it difficult to study in a systematic 
manner. For anesthesiologists, poor recovery is often relayed by the surgeon days or weeks after the 
event, and it is usually categorized as an adverse outcome. 
 
Research tools such as the Aldrete (1)  or the QoR (2, 3)   scales, focus on early physiological recovery,  
or the immediate perioperative period.   These recovery scores are not sensitive enough to measure the 
rate of recovery (change over time) and have not been designed for repeated measures. They are also 
inadequate to identify poor cognitive recovery. 
 
In 2007, an international group of anesthesiologists and neuropsychologists formed an advisory board to 
create a new quality of recovery scale. The aim was to produce a tool that was simple to perform, but 
sensitive enough to detect change in multiple domains of recovery over time. The initial validation 
experiment included over 700 patients, and this work has been published in Anesthesiology. It is called 
the Postoperative Quality Recovery Scale (PostopQRS) (4). Six domains of recovery are identified: 
physiological, nociceptive (pain and nausea) emotive (anxiety and depression), functional recovery 
(return of activities of daily living), cognitive recovery, and an overall patient perspective domain including 
satisfaction. The scale is completed prior to surgery to provide baseline values, and then repeated at 


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user-defined intervals. From some of the subsequent discriminant validation studies, time points have 
included early and late measures such as 15 minutes, 40 minutes, 1 and 3 days, and 3 months after the 
completion of anesthesia (typically defined as after the last surgical stimulation). Recovery is broadly 
defined as return to baseline values or better, except for the cognitive domain where a tolerance factor is 
included to allow for normal performance variability, such that patients are allowed to perform a little 
worse than baseline as still be scored as recovered (5).  Because repeated tests tend to have a learning 
effect, the cognitive domain uses parallel forms, and only a small learning has been shown (5).  
 
One of the most important benefits of the PostopQRS scale is that it enables recovery to be quantified 
and measured. This makes it possible to compare different interventions with the express purpose of 
developing clinical interventions to improve quality of recovery. The PostopQRS offers a tool to provide 
the recovery process to be examined. There are no other tools in existence that provide a 
comprehensive, sensitive assessment of the multiple aspects or domains of recovery, and is yet relatively 
simple to perform. Validation studies have been performed and show good discriminative ability (5-8). 
Ease of use is facilitated by using a web-based data entry system and the ability to use the telephone to 
conduct surveys after discharge form hospital. Telephone survey has been shown to be equivalent to 
face to face interviews using the PostopQRS (5). Further, the PostopQRS allows users to drill down to 
identify which recovery domain is affected for individuals in real time as well as for group audit. 
 
Quality of recovery after operative laparoscopy 
The majority of the literature compares different operative techniques with outcome measures aimed at 
specific complications or length of stay. Few studies include quality of recovery or quality of life measures 
as secondary endpoints (9-12). However, for potential benefits relating to the use of sugammadex, there 
are a few studies primarily centered around deep neuromuscular block (DNB) facilitating low 
intraabdominal inflation pressures. Most outcomes relate to operative conditions with little data on patient 


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centered outcomes especially after discharge.  The inclusion of sugammadex is to permit the use of DNB, 
and most comparative groups (of moderate block) are reversed with neostigmine.  
 
It has been shown that more patients can be operated on with low intraabdominal pressure with DNB, 
and that operative conditions are rated as better in more patients with DNB (13, 14), though it is not 
absolute and there are frequent crossovers. That is, there are patients with moderate block and low 
pressure, and equally patients with DNB requiring high inflation pressures. The very few data on patient 
centered outcomes show reduced pain and nausea after DNB (13, 15-17), but lack of evidence of benefit 
for other recovery outcomes. This paucity of data has been stressed by review articles and editorials that 
DNB is associated with a modest effect on improving operating conditions but very little data to identify 
recovery benefits (13, 18) 
 
Sugammadex is an effective drug to reduce deep neuromuscular blockade 
There is no clinical question that sugammadex is highly effective in reversing neuromuscular blockade 
with rocuronium or vecuronium. This has been the subject of a Cochrane review which included 18 
randomized trials, showing that sugammadex can reverse blockade with rocuronium or vecuronium 
independent on the depth of block, and superiority to neostigmine (19). This aspect of sugammadex does 
not require further study. This translates to a low incidence of residual blockade in the PACU compared to 
neostigmine reversal. The "safety" benefit to using sugammadex has been proven, but this does not 
necessarily translate into better outcomes. Sugammadex, however, is an enabling drug to facilitate deep 
neuromuscular blockade, allowing the anesthesiologist to continue that block until the end of surgery and 
reliably reverse the block. This is just not possible with neostigmine reversal, as one must wait until a train 
of four count of at least 2 twitches (or TOF ratio > 0.7) to safely reverse the block with neostigmine. 
 


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2.2. Objectives and hypothesis 
Objectives 
1.  To identify whether the rate/quality of recovery is affected by deep neuromuscular block (DNB) and  
reversal with sugammadex versus light/moderate neuromuscular block reversed with neostigmine in 
patients undergoing operative gynecological or abdominal laparoscopic surgery of at least 1-hour 
duration. 
 
Hypothesis 
1.  The technique of deep neuromuscular block and  reversal with sugammadex will result in improved 
quality of recovery, including cognition, compared to the current standard of care technique using 
light/moderate neuromuscular block reversed with neostigmine in patients undergoing operative 
gynecological or abdominal laparoscopic surgery of at least 1-hour duration. 
 


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3. Study Methods 
3.1. Trial Design 
Parallel randomized trial with allocation ration 1:1. The trial was registered prior to commencement and 
conforms to CONSORT guidelines. 
The study was conducted in secondary and tertiary hospitals, which included an active laparoscopic surgery 
unit for gynecology and abdominal surgery.  
 
3.2. Randomization 
The randomization sequence was produced using a computer- generated randomization sequence, in 
unequal blocks and stratified for gynecological and abdominal surgery. Concealment was undertaken by 
placing the card containing the allocation information in double opaque sealed envelopes, and 
concealment was maintained until after recruitment and the patients was admitted to the operating 
theatre. The treating anesthesiologist opened the envelopes to reveal the allocation. A non-participant in 
any process of the study prepared the envelopes prior to recruitment. A copy of the randomization 
sequence was stored in a separate databank, which is password protected and not made available to the 
investigators until the completion of the study. 
 
3.3. Sample Size 
Sample size estimates were based on the primary outcome of cognitive recovery at 1 week after surgery, 
and a clinically important difference in cognitive recovery at 1 week after surgery of 15%. Estimates of 
cognitive recovery were based on prior PostopQRS research and using multiple ages and surgical 
cohorts. It was estimated that the cognitive recovery for this cohort and duration of surgery would be 85% 
if there was good recovery. Using a two tailed estimate and Chi-squared analysis, alpha of 0.05, and 
power of 90%, with 1:1 allocation ratio; the sample size required to detect an absolute difference of 15% 


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was 161 per group, which was rounded up to a total sample size of 350  patients to account for potential 
non-completion of the study  
 
3.4. Framework  
Two-center double-blind, placebo-controlled, parallel-group, randomized, phase IV study with 1:1 
allocation ratio. 
 
3.5. Statistical interim analyses and stopping guidance 
Due to the small study size, there was no planned interim analyses, nor stopping rules defined. 
 
 
3.6. Timing of final analyses – timeline of study 
Allocation was revealed after the last data collection time point of the last participant enrolled. Analysis 
followed after this point.  
 
 
3.7. Timing of outcome assessments 
Outcome assessments were undertaken at baseline, prior to surgery, immediate recovery parameters 
were measured in recovery at 15 and 40 minutes following the cessation of anesthesia. Outcomes were 
also measured at days 1, 3, 7, 14 and 1 and 3 months.  


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4. Statistical Principles 
4.1. Statistical significance 
A two-sided P<0.05 defined significance for the primary outcome. 
 
4.2. Adjustments to the statistical significance  
P <0.01 defined significance for secondary outcomes in order to reduce the risk of type I error. 
 
4.3. Confidence intervals 
95% Confidence intervals were reported for all effects where appropriate. 
 
4.4. Adherence and Protocol deviations 
a. Adherence to protocol was defined by the correct allocation at the correct dose at the 
correct time.  
b. Adherence was presented in the CONSORT flow chart. 
c. Protocol deviations were recorded as incorrect dose or timing, or supplemental use of 
midazolam. 
4.5. Definition of analysis populations  
Patients were analyzed on an intention-to-treat basis.


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5. Trial Populations  
5.1. Screening 
Patient screening was performed by a researcher who was not part of the treating team. The screening 
log was collected and stored as an excel file on the University of Melbourne server. This includes the 
reasons for screening failure and date of screening. 
 
5.2. Eligibility Criteria 
Inclusion: 
1. Adult participants undergoing operative gynecological or abdominal surgery under general 
anesthesia of at least 1 hour duration 
 
Exclusion: 
1. Participants, who are not fluent in English will be excluded, as they may be unable to answer the 
recovery questionnaire adequately.  
2. Participants undergoing diagnostic laparoscopy only 
3. Participants <18 years of age 
4. Current pregnancy 
5. Known allergy to rocuronium, neostigmine or sugammadex, or desflurane 
 
5.3. Recruitment 
A CONSORT flow diagram was constructed to illustrate the flow of recruitment throughout the study. 
Recruitment was performed by a study investigator who was not part of the treating team and remained 
blinded to the allocation. Written informed consent was obtained prior to allocation.  
 


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5.4. Withdrawal 
Withdrawal of the patients can occur at any point from the initial baseline up to the final completion of 
the study for that particular participant at 3mths after surgery, this may be in the form of refusing to 
continue with the study. Patient are lost-to-follow up if they are not present for their follow-up 
assessments in their final timepoint at 3 months. 
 
5.5. Baseline Patient Characteristics 
The following characteristics was summarized in a table format as either Mean ± SD  (continuous data) 
on (%) (discrete data): Age, Gender, ASA status, Obesity, Education, Alcoholic consumption, Smoking 
status, Pre-existing conditions, Problems with previous anesthesia, Employment Status.. 
 


Statistical Analysis Plan V1 17/06/2019 
 
 
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6. Analysis 
6.1. Outcome definitions 
Primary outcome  
The most sensitive recovery domain of the Postoperative Quality of Recovery Scale to the effects of short 
acting drugs and avoidance of neostigmine is cognition. The primary outcome was the cognitive domain 
at 1 week after surgery, where it is expected that most of the acute inflammation will have resolved, and 
analgesia requirements would be minimal.    
  
Secondary outcomes  
1. Recovery for all domains and within domains at the other time points of measurement (15 minutes, 40 
minutes 1 day, 3 days, 1 and 2 weeks, and 3 months following cessation of anesthesia). The domains of 
recovery are physiological, nociceptive, emotive activities of daily living, cognitive and overall patient 
perspective.  
  
2. Compliance with protocol to ensure deep block or light/moderate block, and correctly assigned 
anesthetic.   
  
3. Anesthesia, surgical (first incision to last stitch), operating room, and PACU times, and hospital length 
of stay  
  
4.  Incidence of persistent neuromuscular block (TOF < 4 twitches or visible fade, or TOF ratio < 0.9) 
upon arrival in the PACU.  
  
5. Surgical operating conditions measured by maximal inflation pressure required for surgery, and 
number of times that organ movement occurred (due to diaphragmatic movement or abdominal wall 


Statistical Analysis Plan V1 17/06/2019 
 
 
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tone), and overall surgical satisfaction using a 1-5 Likert scale (1 = very unacceptable, 2 = unacceptable, 
3 = acceptable, 4 = good, 5 = excellent).  
 
6.2. Analysis Methods 
A Fisher’s Exact test was used to analyze the primary outcome of cognitive recovery at week 1 following 
laparoscopic surgery. A Generalized Linear Mixed Model (GLMM) test was used to analyze the recovery 
within and across all domains over time, including patient satisfaction. For the secondary outcomes, 
GLMM was used for analysis of the recovery domains and a T test was used for continuous data. 
 
 
6.3. Missing Data 
Missing Data was not expected to be substantial, so it was not imputed, and incidence of recovery was 
analyzed using available data only. 
 
6.4. Additional Analyses 
No additional analysis was conducted. All analyses have been previously mentioned. 
 
6.5. Harms  
Harms will be defined on an incident basis, and where the trial drug is a likely contributor to the specific 
harm. 
 


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6.6. Statistical Software 
GENSTAT V18 (VSNi International Ltd) was used to perform the GLMM test, and SPSS V21 (SPSS Inc) was 
used for all other analyses. 
 
6.7. References 
This survey was conducted using the online survey tool located at www.postopqrs.com. The study related 
information from both the centres was transferred onto the database in a non-identifiable manner. The 
database only allows de-identified information to be stored and only investigators have access to the data. 
It complies with international privacy laws. The databank is located at the City University Hospital in 
London, United Kingdom. This database allows us to score participants’ recovery automatically and send 
that information back to the investigating team. This de-identified data was used as pooled data to help 
establish international “benchmarks” for recovery outcomes following endoscopy procedures.  
 
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