Laparoscopy Clinical Trial
Official title:
A Randomized Trial of Deep Neuromuscular Blockade Reversed With Sugammadex Versus Moderate Neuromuscular Block Reversed With Neostigmine, on Postoperative Quality of Recovery
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.
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.
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