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A 2021 Review of What's New in the Surgical Application and Reversal of Neuromuscular Blockade

  • Authors: J. Ross Renew, MD; Sorin J. Brull, MD, FCARCSI (Hon)
  • CME / CE Released: 12/21/2021
  • Valid for credit through: 12/21/2022
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Target Audience and Goal Statement

This activity is intended for anesthesiologists, surgeons, neurologists and nurses. 

The goal of this activity is to provide anesthesiologists, surgeons, and nurses with the most up-to-date information on new data regarding how best to avoid residual paralysis following neuromuscular blockade (NMB) in surgical patients.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • New guidelines relating to the safe and effective use of NMB in surgical settings
    • Regulatory updates relating to medications used in NMB in the surgical setting
    • New data related to advances in NMB during anesthesia


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  • J. Ross Renew, MD

    Assistant Professor of Anesthesiology
    Vice Chair for Research
    Department of Anesthesiology and Perioperative Medicine
    Mayo Clinic
    Jacksonville, Florida


    Disclosure: J. Ross Renew, MD, has the following relevant financial relationships:
    Grants for clinical research from: Merck

  • Sorin J. Brull, MD, FCARCSI (Hon)

    Emeritus Professor of Anesthesiology
    Department of Anesthesiology and Perioperative Medicine
    Mayo Clinic
    Jacksonville, Florida


    Disclosure: Sorin J. Brull, MD, FCARCSI (Hon), has the following relevant financial relationships:
    Speaker or a member of a speakers bureau for: Senzime AB
    Grants for clinical research from: Merck, Inc.
    Stocks, stock options, or bonds from: Senzime AB


  • Frances McFarland, PhD, MA

    Associate Medical Education Director, Medscape, LLC


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  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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A 2021 Review of What's New in the Surgical Application and Reversal of Neuromuscular Blockade

Authors: J. Ross Renew, MD; Sorin J. Brull, MD, FCARCSI (Hon)Faculty and Disclosures

CME / CE Released: 12/21/2021

Valid for credit through: 12/21/2022


Activity Transcript

J. Ross Renew, MD: Hello. I'm Ross Renew, assistant professor of anesthesiology and vice chair for research in the Department of Anesthesiology and Perioperative Medicine in Mayo Clinic in Jacksonville, Florida. Welcome to this program titled "A 2021 Review of What's New in the Surgical Application and Reversal of Neuromuscular Blockade."

Joining me today is my colleague Dr Sorin Brull, who is a professor emeritus of anesthesiology in the Department of Anesthesiology and Perioperative Medicine, also at Mayo Clinic in Jacksonville, Florida.

Over the next half hour or so, we will discuss what's new in 2021 as far as neuromuscular blockade. Let's first start with a little background.

Adequate recovery following neuromuscular blockade management is defined as a train-of-four ratio exceeding 0.9. Anything less than this value is evidence of postoperative residual weakness. Unfortunately, this is a very common occurrence following neuromuscular blockade in the perioperative setting. Recent evidence has shown that up to 65% of patients can have evidence of postoperative residual weakness at the time of tracheal extubation. Extubating a patient prior to achieving adequate recovery can expose them to critical respiratory events. In addition to critical respiratory events, a number of other complications have been associated with postoperative residual weakness.

Unfortunately, residual weakness can be difficult to diagnose and not completely obvious. Patients that have low levels of residual weakness may pull adequate tidal volumes on a ventilator, or they may have adequate grip strength, making this challenging to confirm with clinical assessment. Factors that increase this risk of residual weakness include the obese patient with an elevated body mass index (BMI), shorter operations that require deep levels of blockade, not using a quantitative monitor, utilization of a peripheral nerve stimulator at the face. It's tough to predict which patients will experience postoperative residual weakness. And really, we should be monitoring all of these patients to try to confirm adequate recovery.

Fortunately, there are several strategies that have emerged to combat this patient safety threat. The use of long-acting neuromuscular blocking agents such as pancuronium absolutely needs to be avoided in modern anesthesia practices. Reversal and monitoring represent evidence based best practice in combating this issue.

Let's look at what's new in 2021. Sorin, can you talk a little bit about the expanded indication for sugammadex?

Sorin J. Brull, MD, FCARCSI (Hon): Thank you, Ross. As many clinicians may already know, sugammadex is now indicated for reversal of neuromuscular block in pediatric patients aged 2 years and older. So, this decision was made based on a clinical trial of 288 patients, in which they noted that sugammadex, actually, as we saw in adults, the recovery time was much shorter. And it's interesting and also important to note that like in adults, the effects were pretty much consistent across the age cohorts.

In a study just published in the Journal of Cardiothoracic and Vascular Anesthesia, 60 children who were undergoing cardiac surgery were randomized to receive either sugammadex or neostigmine in order to antagonize neuromuscular block. The recovery time was 3 and a half minutes for sugammadex and 76 minutes for neostigmine. The extubation time was 31 minutes for sugammadex and 125 minutes for neostigmine. In the same study, the length of hospital stay was actually shorter in the sugammadex group. Hospitalization expenses were lower in the sugammadex group despite obviously the drug being more expensive than neostigmine. And the incidence of postoperative atelectasis was actually non-existent in the sugammadex group, whereas it was 20% in those patients who received neostigmine.

We also should recognize that, actually, even before the FDA approval for use in pediatric patients, sugammadex was used off label. And in this survey on the antagonism of neuromuscular blocking agents, 38.9% of clinicians use sugammadex as their primary reversal agent. And 25% use sugammadex exclusively. And unfortunately, only 40% of respondents stated that they always assess neuromuscular block by using some quantitative train-of-four monitoring. In fact, those who primarily use sugammadex assess train-of-four less routinely than those who used neostigmine.

Also important to note is that 53% of the clinicians use sugammadex in postmenarchal girls, which obviously has significant implications on potential unwanted pregnancies, because 38% of the clinicians never bothered to discuss the effects [on] hormonal contraception with a patient or with their family.

So, now that we covered this, can you please briefly discuss our editorial on the use and, I would say, misuse of neuromuscular blocking agents and their antagonists.

Dr Renew: Sure. Thanks, Sorin. One of the features that I thought was interesting is the number of safety concerns as it relates to using sugammadex in pediatric care. The concerns were raised over bradycardia, laryngospasm and the impact on hormonal contraception, like you mentioned. It's alarming that nearly 40% of the respondents do not discuss this potential complication. Another concern was the potential for hypersensitivity reactions associated with sugammadex.

But the most common concern related to neuromuscular blockade in pediatric patients was postoperative residual weakness. Postoperative residual weakness is still something at the front of pediatric anesthesiologist's brains and something to improve. So, there's this notion that if you have sugammadex, you don't necessarily need to monitor your patient. Well, these researchers found that up to 9.4% of patients, when given sugammadex without a monitor, still had residual weakness.

In our editorial also, we called for pediatric anesthesiologists to reevaluate their neuromuscular monitoring practice. Whether it's an adult or a pediatric patient, we need to be utilizing our quantitative monitoring to confirm that our pharmacologic interventions have their desired effect. We also endorsed the international consensus statement that came out several years ago calling for the use of quantitative neuromuscular monitoring whenever neuromuscular blocking agents are utilized, independent of whether it's a patient that is an adult or a child. This international panel of experts developed several important statements that we can translate into our clinical practice.

In our editorial, we also pointed out several lessons related to neuromuscular blockade management in the pediatric population. First, independent of FDA approval, sugammadex is still widely used in pediatric patients. In pediatric patients also, the use of sugammadex without quantitative monitoring can also lead to residual weakness. They can certainly have significant complications. We also point out in our editorial that neuromuscular monitoring in children is feasible even in neonatal infants. Quantitative monitors are no longer just a tool to enhance patient safety in adults, but also can be implemented in pediatric population.

And this leads us to, really, a big highlight from 2021, in which Edwards and colleagues published an analysis of the impacts, the financial impact, of universal quantitative monitoring at Temple University. This is a well-designed quality improvement project in which the investigators looked at 100 patients undergoing elective surgery under general anesthesia requiring neuromuscular blockade. And interestingly, the incidence of residual weakness at this institution was not that different from other previous multicenter reports. Sixty percent of patients did not have adequate recovery at the time of extubation.

So with that baseline level of residual weakness at their institution established, they then tried to extrapolate this incidence of residual weakness and broaden it to determine what the financial impact, of various complications may be based on patients having residual weakness. They found that over a year's time, about 2.5% of their patients had postoperative pneumonia, 2.7% of their patients had respiratory failure postoperatively that required re-intubation. When we take some standard assumptions and look at the average cost of care, it costs over $50,000 when a patient develops pneumonia or requires re-intubation versus $14,000 in a patient who did not have these complications.

Looking at a couple conservative estimates at their institution, if they delivered 7500 anesthetics a year, requiring general anesthesia and neuromuscular blockade and reversal, this would suggest that 4500 surgical patients experienced postoperative residual weakness. Taking their frequency of postoperative pulmonary complications, now, we have 189 patients in a year's time that have experienced postoperative respiratory compromise based on inadequate neuromuscular blockade management. And when we look at that marginal cost per patient, these researchers estimated that the total annual cost of a pulmonary complication at their institution is nearly $7 million. And when we compare that to the cost of monitoring our patients, looking at $162,000 per year, it becomes very obvious quickly that utilization of quantitative monitoring is potentially a cost savings benefit. If we could only prevent just 5 patients from having postoperative pulmonary complications, then we've paid for the cost of quantitative monitoring throughout an institution.

Sorin, was there anything presented at this year's ASA in San Diego as far as monitoring goes?

Dr Brull: Sure. As we all know, one of the major limitations of many of the currently available neuromuscular monitors is the location of monitoring, particularly when the arms may not be available. So, this is important because we know that monitoring of the facial muscles results in significant residual neuromuscular block.

So, this study compared the thumb and the great toe monitoring using electromyography. So overall, the onset time from administration of a neuromuscular blocking agent until train-of-four count of zero was faster at the foot than at the hand. The mean recovery time from sugammadex administration until train-of-four ratio was recovered to a ratio of 0.9 or above was 220 seconds at the foot and 197 seconds at the hand. I think those differences are relatively small statistically, and they're even smaller when you talk about the clinical relevance. So, I think it's fair to say that the great toe is a feasible alternative site when the arm and the adductor pollicis of the thumb is not available.

In one of the first studies of electromyography in pediatric patients, following antagonism of neuromuscular block, the baseline amplitude recovered to a mean of 6 millivolts. And the train-of-four ratio recovery to a mean of 0.84. So, this really is, I think, one of the first studies to document that EMG can be used in pediatric patients as small as 20 kilograms.

So, this study included 15 patients. The authors concluded that EMG is a more precise and more reliable monitor in restricted arm settings where the clinician doesn't have access to the thumb. It was also interesting that respondents deemed the electromyography the better and easier to use monitor.

In this study in the Journal of Anesthesiology, contractions and muscle action potentials from the same adductor pollicis muscle were measured simultaneously by acceleromyography- and electromyography-based neuromuscular monitors. The authors concluded that the EMG-based monitor had higher precision and greater repeatability than acceleromyography and that electromyography provides a better indication of adequate recovery and readiness for safe tracheal extubation than acceleromyography.

So, similar to the study mentioned earlier in adults, this study of EMG monitoring in the restricted movement surgical setting was performed in 18 pediatric patients. And basically, the authors pretty much show that monitoring at the adductor pollicis using electromyography is not only doable, but it appears to be preferable in pediatric patients.

So, let's go back to the question of sugammadex versus neostigmine. And this is just a brief reminder about a Cochrane Systematic Review and meta-analysis that was published just a few years ago. As the authors mentioned, sugammadex reverses neuromuscular block more rapidly than neostigmine and is associated with fewer adverse events.

A multicenter observational matched cohort study was published this year. The patients were undergoing elective non-cardiac surgical procedures. It was pretty clear, based on their analysis, that sugammadex reduced the risk of pulmonary complications by 30%.

This included 200 patients undergoing thoracic surgery. The percent of patients with a train-of-four ratio less than 0.9 was 80% in the neostigmine group and 6% in the sugammadex group. And then, at the PACU admission, the differences were 61% incidence of residual weakness in patients treated with neostigmine as opposed to 1% of those patients who are treated with sugammadex. Additionally, the authors noted less optimal operative conditions in the neostigmine group. And the patients also had more symptoms of muscle weakness in the recovery room if they received neostigmine antagonists.

When we look at the intraoperative coagulation parameters in patients undergoing thyroidectomy, we see that the activated partial thromboplastin time, PTT, was slightly increased in the group receiving sugammadex, as was the reaction time, although these changes were not really clinically significant.

In a recently published systematic review and meta meta-analysis of 7 studies with 386 patients undergoing bariatric surgery, the mean time for reversal was 2 and a half minutes for those receiving sugammadex, and it was 18 minutes for those receiving neostigmine. What's really important to note also is that 21% of patients who received sugammadex had composite adverse events, as opposed to almost 53% of patients who receive neostigmine. And this difference was pretty statistically and I would say clinically significant.

So Ross, it also looks like a couple of presentations of this year's anesthesiology meeting also suggested that actually neostigmine may be preferable. So, can you talk about that?

Dr Renew: Thanks Sorin. There's a couple abstracts that I think add a little bit more to this question on optimal reversal agent selection. The first one was Harwood and colleagues. And they looked at a large retrospective cohort of their patients and matched them based on whether they got sugammadex or neostigmine. They found patients who got sugammadex more likely to have postoperative pulmonary complications. They had slightly higher 30-day mortality and were 4.79 times more likely to have a readmission within 30 days of their operation and had a slight increase in their chance of getting admitted to the ICU.

When you look at some of the discussion and talk with some of these investigators, they really attribute this to an inability to control for all of the comorbidities that go into it. And by their own admission at their institution, their standard practice is that sugammadex is really triaged and utilized in sicker patients at their institution. Putting into context of other literature, they were unable to show similar gains in switching from neostigmine to sugammadex.

Another study tried to look at the effects of sugammadex versus neostigmine in very shallow levels of neuromuscular blockade. In addition to seeing if the patients received sugammadex or neostigmine, they surveyed the anesthesiologist as to why they chose whichever drug that they chose. And they found that only about a quarter of the time, the reversal agent was even discussed between the interim provider and the anesthesiologist. Neostigmine was chosen because it was cheaper than sugammadex in almost 38% of cases. Sugammadex was chosen in 90% of cases due to its efficacy.

Interestingly, they found that in an uncomplicated patient who's near spontaneous recovery, has a very shallow level of blockade, sugammadex versus neostigmine, there was really no significant difference in the time from reversal to tracheal extubation.

A similar interesting endpoint to try to justify the additional cost of sugammadex is looking at PACU length of stay. And this has been investigated before. But this looked at one center where they tried to determine if the reversal agent had an impact on the length of stay in the recovery room. And what they found is the median time in the recovery room, it really didn't change based on the reversal agents that were utilized. In fact, the sugammadex group was estimated to be in the PACU 13% longer than in the neostigmine group. Again, I think, this adds to the picture when we start thinking about which reversal agent to select. But I worry that PACU length of stay is a bit of an arbitrary endpoint The determinants of PACU length of stay are certainly multifactorial and trying to just identify one medication as a cause of that can be challenging and may need further investigation.

Adamgammadex is structurally related to sugammadex and is a binding agent. However, there are some slight modifications to its structure. And this was really developed in an effort to try to decrease some of the hypersensitivity and anaphylactic and anaphylactoid reactions that have emerged with the use of sugammadex. This paper looked at various doses of adamgammadex. And they found that as you increase the dose of adamgammadex, you're able to more quickly reverse deep levels of blockade, similar to sugammadex at 4 mg/kg. There were no instances of hypersensitivity reactions. But, again, a small cohort and something that's going to need to be looked at with much, much bigger numbers before we can comment on whether or not this new drug in the same class as sugammadex actually has less hypersensitivity reactions.

We've noticed that more and more surgeons, particularly when doing laparoscopic or robotic surgeries, are requesting deep levels of blockade in which the diaphragm may be completely paralyzed, or maybe when your train-of-four count is zero and you're only having post-tetanic counts. I think the literature is a little controversial on this. Sorin, are you familiar with any new updates or items to keep an eye on as it relates to deep level levels of blockade?

Dr Brull: So, in the argument for deep neuromuscular block, Glenn Murphy supported the use of deep neuromuscular block in laparoscopic procedures. The editorial highlighted the potential benefits of deep neuromuscular block, which included improved surgical conditions, reduced patient movement, reduced bleeding, reduced pain postoperatively, which may decrease the use of opioid analgesics, reduced need for increased intra-abdominal pressure during the operation. It has potentially optimal protective lung ventilation strategies. And then, it has been shown that, at least in the laparoscopic procedures, deep neuromuscular block has been associated with lower 30-day readmission rates.

In patients undergoing total hip replacement surgery, the interleukin 6 increased significantly less in the patients undergoing deep neuromuscular block than in those undergoing moderate neuromuscular block. Interestingly also, the amount of postoperative bleeding was also significantly greater in the moderate neuromuscular group than in the deep neuromuscular group. The postoperative delirium, which is one of the potential complications that we worry about, particularly in the elderly following general anesthesia, there were no significant differences between the 2 groups.

In another study that was published this year, patients underwent laparoscopic resection of colorectal tumors. And as we saw before, the pain level postoperatively was lower in the patients undergoing deep neuromuscular block, both at rest and during coughing at various times postoperatively. The number of bolus attempts by the patient to self-medicate with opioid analgesics was lower in the deep neuromuscular group. The number of boluses delivered was significantly lower in the deep neuromuscular group in the first postoperative day. And the number of rescue analgesics was lower in the deep neuromuscular group on postoperative day number 2. And finally, the deep neuromuscular block group showed lower frequency of postoperative nausea and vomiting, probably not directly attributable to the intraoperative pressure per se, but to the lower amounts of opioids that they required.

In this study by Lee and colleagues, again, published this year, 80 non-obese patients undergoing laparoscopic gastrectomy in the reverse Trendelenburg position were investigated. And the optimal surgical field conditions were rated by surgeons in 87% of the times in the deep neuromuscular group, versus only 72% of the times in the moderate neuromuscular block group. Also, the percent of patients who were maintained under what they call good or optimal conditions throughout the induction of pneumoperitoneum was higher in the deep neuromuscular group. And there were no significant differences in the percentage of recovered patients.

Heidi Lewald is the author of the argument against the routine use of deep neuromuscular block, and she actually questions the use of deep block in laparoscopic procedures. And she highlights that the evidence that deep neuromuscular block improved surgical conditions is not really as clear as we think, at least in terms of improving outcomes. For instance, not all studies reported beneficial effects. Murphy also acknowledged this in his pro editorial. And that most studies have assessed carefully selected patients undergoing a single type of procedure. Also, she noted that differential use of neuromuscular block during laparoscopic surgery might be better and that higher doses in deeper block increased the risk of residual neuromuscular block in postoperative complications.

This was a single-center study of deep versus moderate depth of block during renal surgery with sevoflurane anesthesia. And they found, actually, that there was no difference between moderate and deep block in terms of the Leiden surgical rating scale scores and no differences in prolonged hospital admissions or unplanned postoperative readmissions.

So, we can say that recovery of gastrointestinal (GI) and urinary function, which we haven't mentioned so far, are actually other areas of interest. And perhaps Ross has some new information about this?

Dr Renew: Yeah, thank you. I think that if we're trying to look at effects on things that we might not necessarily associate with reversal, such as the GI tract and urinary system, there's been some neat stuff to come out pretty recently.

This is a pilot study of non-obese adult females undergoing minor surgery. They randomized patients to either receive sugammadex or atropine with neostigmine, kind of the traditional reversal cocktail. And with the primary outcome of looking at the lower esophageal barrier pressure at 5 different time points during emergence in patients who had a total intravenous anesthesia (TIVA), with the idea that having reversal agents that have cholinergic effects and muscarinic effects, such as neostigmine and atropine or glycopyrrolate, these could have implications on GI motility.

And what these investigators found is that the pressure values were positive in all patients even under muscle paralysis and general anesthesia. The tone of that lower esophageal was maintained to some degree under anesthesia, but it increased significantly in both groups as patients recovered from both general anesthesia and muscle paralysis. And it didn't matter if these patients got reversed with sugammadex or neostigmine. And this is one of the first investigations to try to quantify the lower esophageal sphincter tone at what's really a critical point, when patients are waking up or getting ready to remove the cuff endotracheal tube and potentially expose them to aspiration risk.

Along those same lines, there's been a couple of retrospective efforts that have compared sugammadex with neostigmine/glycopyrrolate as it relates to the first flatus or first bowel movement. And this effort by Hunt and colleagues looked at reversal with neostigmine. They looked at 224 patients. And they found that it was almost half a day faster to first bowel movement with sugammadex than neostigmine glycopyrrolate. There was no significant difference in postoperative ileus, postoperative nausea, vomiting or hospital length of stay. And no patient in either group actually had residual weakness that they could detect based on their retrospective review. But again, single center, not prospective, not randomized. And this investigation was similar with a previous report looking at patients that had intraperitoneal surgery over 2016 to 2017. The introduction of sugammadex had a significant decrease in the time from reversal to first bowel movement.

Postoperative urinary retention is also a complication that can prolong PACU length of stay. It can actually lead to unplanned hospital admissions in the extreme instance. And so, this effort here wanted to investigate the role of reversal agent as it relates to postoperative urinary retention. They found that 2 of their 181 patients that received sugammadex, or about 3%, had postoperative urinary retention. We can compare that with the 16 patients, or 15% of patients, that received neostigmine had urinary retention. These data reach statistical significance and suggests that sugammadex has less postoperative urinary retention than neostigmine/glycopyrrolate. And that's even after we control for other confounders such as opioid administration.

And so, with this mounting evidence that GI motility is returning to normal faster and that the bladder function is returning to normal faster by using agents such as sugammadex, I think, we're really starting to see evidence build and mount that the decisions we make in the operating room, as it relates to neuromuscular blockade management, have implications on postoperative recovery. We're starting to get some evidence that it's probably not the sugammadex in of itself, it's probably just avoiding the cholinergic muscarinic effects of neostigmine and glycopyrrolate, where we can realize some of these gains and return to homeostasis.

And in this era of pushing enhanced recovery and pushing patients to return to their baseline status sooner, certainly, the role of optimal neuromuscular blockade management is absolutely critical. In fact, the Enhanced Recovery Society, in their consensus statement and their guidelines, go on to strongly recommend quantitative neuromuscular monitoring and reversal.

We've talked about a lot of stuff today. And I just like to kind of sum up some of the more interesting topics that we've addressed today.

Firstly, we address the sugammadex and its expanded indication in the pediatric surgical population. We compared sugammadex and neostigmine and showed some evidence that it may restore neuromuscular function sooner than neostigmine and have less postoperative residual weakness. But it does have some added costs to it.

We also looked at some of the literature out there on GI motility and bladder function as it relates to the decision on which reversal agent to use and enhanced recovery.

We also looked at some evidence that the cost of residual weakness can be pretty significant. And offsetting that value just by a little bit could easily offset the cost of neuromuscular monitoring and introducing it into your practice. Utilization of quantitative monitoring is not only best for patient safety but may also have cost implications as well.

We also talked about the use of deep neuromuscular blockade and its role in laparoscopic and robotic surgery. This literature remains controversial.

Sorin, I want to genuinely thank you for this outstanding discussion that we've had today. I always learn something when I get to join you for a conversation on something that I'm passionate about. And I really appreciate you bringing to light some of the newer literature with us.

Dr Brull: Thank you very much, Ross. I truly enjoyed it as well.

Dr Renew: And thank you for participating in this event. Please continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.

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