Is it important to reverse to a train-of-four target of 90%? Part 2

Welcome back to Depth of Anesthesia. I'm David Hao and I'm an anesthesia resident at the Massachusetts General Hospital. This week's episode will be featured on Anesthesiology News, a go-to resource for the latest updates in our specialty. In the past few days, I've done a complete overhaul of our website at depth of anesthesia. com, and I'm super excited to be partnering with QXMD, makers of the Read App. Read is a personalized medical journal that allows one-tap access to full-text articles.

We'll be working with them in the coming weeks to compile references in a collection for each depth of anesthesia episode, so be on the lookout for that. This is part two of my series with Dr. Daniel Saddawi-Konefka on reversal of neuromuscular blockade. It's been almost an entire year since part one, but we're finally ready to finish the story. Dan welcome back to the show. David, it's great to be back.

It's been too long, but uh I'm finally uh I'm glad we're finally getting this done Before we even get started with this case, I know you've been doing incredible work in the mental health space with the Emotional PPE project. Do you want to share a little bit about this resource with our listeners? Oh yeah, definitely. Thanks for the opportunity. So um the Emotional PPE project is a project for any healthcare worker, not just uh anesthesiologists or not just physicians.

The idea was uh early on in the COVID pandemic, we realized that one of the most limited resources would be our mental health, our resilience. And we were fortunate to find that across the country uh an outpouring of support from licensed mental health uh therapists. So what the project is is basically you can go on there Pick your state and find a number of licensed therapists who are willing to provide you care for free. We set this up because there are a whole lot of barriers to people getting help. whether that's fear of licensure uh implications or cost or decision paralysis. But really it's it's one click.

The project itself does not collect any information about the folks who use it. It just it's a directory that allows you to connect directly with uh with therapists who are all volunteer and wanting to do this to to do their part to help. You can uh find it at emotional ppe. org. So Dan, what kind of people should be using this this platform and resource? Oh, that's such a great question.

I think there's this uh this unfortunate stigma in uh in healthcare that you have to be on death's door to use something or you know if you cough up a lung, shove it back in and get back to work. And I think that really is not a good way of being and it's it's contributing to this this epidemic of burnout that we have in in medicine. So I think I think it's anything that you're feeling. You know, there's no reason to feel ninety-five percent of how you normally feel. If you're even a little bit below where you think you ought to be, just reach out and to talk to someone.

Uh I've used it myself. I find it quite helpful. And just to clarify for our listeners, are the services free and anonymous? Yeah. Well so the project doesn't collect any information.

I suppose that the therapist you talk with would would know who you are, but uh there's nothing beyond that. And one of the big advantages of this is you can access these mental health uh experts online. So it's not like you have to meet with them. You can just log on, set up a time and date and virtually speak with them, right? That's right.

It's 100% telehealth. Awesome. Well, thanks for sharing this resource with our listeners, Dan. It's obviously been a stressful year, and I know this resource has the potential to really help clinicians across the country. So thank you for your work in this space.

Yeah, it's an exceptional team of volunteers that's been working on this. Um uh thank you very much for for giving it a little airtime. Oh, absolutely, Dan. Thanks for sharing. Moving on to our case for today, as our listeners probably don't remember, is that of a 42-year-old healthy woman who presented for a laparoscopic gynecologic case.

Choose paralyzed on induction with Rocuronium and redose three times. At the end of the case, the resident elicits four twitches with no fade using a facial nerve stimulator. and it's been sixty minutes since the last dose. The resident plans to proceed to extubation, but the attending makes them recheck twitches on the alder nerve, and when the attending feels no fate, they plan to proceed to extubation. We do have a new development in this case, however. Just prior to extubation, the current attending is relieved and the new attending requests a quantitative check of the train of four.

The train of four shows eighty percent and the attending tells the resident that they prefer to wait to a train of four of ninety percent prior to extubation. Dan, would you be able to summarize some of the claims we reviewed in our prior episode and the claims that we'll be reviewing today? Yes, absolutely. And I should I should probably give a disclaimer up front that we in in no way are supporting switching the attending just prior to extubation. That said Some of the things we talked about last time were does it matter what site you check your Twitches at, uh facial versus ulnar?

Uh we also talked about how long you can go since the last dose to decide, oh, it's been long enough, or is there really no No time that's long enough. And can you discriminate feed uh fade just by feeling the strength of the twitches either at the eyebrow or the uh or the thumb. This week it sounds like we're probably going to be looking at more quantitative train-of-four ratio and whether greater than 90%, using that as a threshold, is actually important to achieve prior to extubation. So here are two questions for our listeners to think about. What is the level of your agreement with the claim that a quantitative train of four ratio greater than 90% is important to achieve prior to extubation?

And what is the level of evidence for what you believe? We conducted a survey of our live audience at Mass General back in February and we actually asked this question. We asked, what was the best train of four target for extubation? There were about 40 people who responded, and 91% of the respondents replied more than 90%. And of those respondents, 56 % felt that the evidence was limited.

So Studies existed to support the claim, but might be a bit weaker in terms of being correlations or extrapolations. And twenty-six percent felt that the evidence was strong with randomized control trials. I do want to review a very interesting study that was conducted back in 2010 and published in ANA. It was designed to determine the use of and attitudes towards neuromuscular blocking drugs and monitoring. Interestingly, European respondents were forty percent more likely than their US counterparts to believe that routine use of either conventional or quantitative train of form monitoring would decrease the incidence of residual paralysis.

They also found that routine reversal was less common in Europe at eighteen percent than in the United States at thirty-four And quantitative monitors were only available to 23% of clinicians in the US compared to 70% in Europe. Finally, 20% of Europeans and 10% of Americans never use neuromuscular monitors at all. Now, before we even get into the studies, Dan, what kind of outcome variables would we be interested in looking at? Yeah, that's a really interesting survey. And it I think it uh speaks to some of the differences in in uh practice patterns of opinions that providers have.

So to your question, if we were to have studies What would they want to look at? What would we be interested in looking at to say there is a difference? Well, I think there's a lot we'd like. The the incidence of some of the more rare but serious things limits our ability to have All of the studies address those. So the studies historically have looked at things like pharyngeal and esophageal function.

Some of them look at spirometry measures. There's actually some evidence of attenuation of hypoxic ventilation response. So some studies have looked at that. There's also sort of separate from all of the say lung or breathing functions. Uh it does it just feel unpleasant if you are partially paralyzed.

So that's uh some of the studies have looked just at symptoms. Uh and then other things like PACU length of stay. You know, and of course there are studies that have looked for respiratory events themselves. So let's start the discussion by reviewing some of the literature, examining the origins of train of four targets. And I know the first train of four target that people seem to settle out on was about 0.7 So I think some of this comes from the early studies by uh Ali in particular in the early 1970s.

We'll talk about two. So the first one is called Evaluation of Recovery from Non-Depolarizing Muscular Blockade Using a Digital Neuromuscular Transmission Analyzer. This was published in A in 1973. And you know, it was a very roughly done study, uh, but what they did was they looked uh at train-of-four ratios to see what represented, quote, adequate recovery from uh tubocurarane blockade And what they found was that at a ratio of 0.74, they thought things were, quote, adequ acceptable. And what they meant by that were patients were able to open their eyes widely, cough, protrude their tongue, sustain a headlift for five seconds. and could give a forced vital capacity of at least 15 to 20 cc's per kilo.

That's an absolute measure, not relative to what they could do before. uh and they also had sustained titanic stimulation for five seconds. So that was one of the first studies in nineteen seventy three. A couple of years later, also by Ali and others, uh published in nineteen seventy five, this is in uh BJA. They there's a study they called uh the effect of tubocurarine on indirectly elicited uh train of four muscle response and respiratory measurements in humans. So again, this is by the same group.

And here they're measuring changes in respiratory variables, including tidal volume, vital capacity, inspiratory force, and peak expiratory flow rate And what they found was that uh differences between uh before and after were quote unquote negligible until Train of four ratios were lower than 0.6. At a train of four ratio of 0.7, all the patients were able to sustain eye opening, hand rest, stick out their tongues. Um nine out of ten could uh maintain a five second headlift. So I'm guessing something must have happened for the recommendations to increase the train of four ratio from point seven which was kind of suggested by these studies to point nine, which is the figure I often hear quoted today.

Yeah. Absolutely. So, you know what they what we had initially was just those variables, things like spirometry variables and you know being able to stick out your tongue. And people thought this is this is good, but is it necessarily uh sufficient to say that this is enough. So let's talk about a couple studies related to that.

First one is by Sunman and Company. This is out of Ericsson's group. Uh that's called the incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans Pharyngeal video radiography and simultaneous monometry after atrocurium. So this was published in the year 2000, and this is a volunteer study. And this is one of those that's going to look at uh pharyngeal tone.

They uh did video radiography as well and they really wanted to see what what's pharyngeal function at different train of four ratios uh using uh uh an infusion of paralytic. I think one of the most salient outcomes that they saw was that in train with train of four ratios of a less than 0.9 on video radiography, six out of fourteen volunteers, and remember all they're getting here is this paralytic confusion, nothing else. So at Trainophore ratios of less than 0.9, 6 out of 14 volunteers aspirated, and the upper pharyngeal tone was lower in all of the patient, in all of the subjects at a train of four of less than 0.9. So the second study is another small volunteer study, 12 volunteers.

This is out of Eicherman's group. It's called Excelmiometry of Adductor Polysis Muscle, Predicts Recovery. of respiratory function from neuromuscular blockade. This is published in anesthesiology in 2003. And what they did was they used MRI to measure supraglottic airway and uh the the area of the retropalatal and retroglossal areas, uh and also EMG of the genial glossis. So basically how much obstruction, what's the ability to maintain a patent airway.

And this is all on healthy volunteers. They took it down to a train-of-4 ratio of 0.8. And at a train of 4 ratio of 0.8, the retropadal and retroglossal areas were significantly decreased. And tongue protrusion and EMG, this is a little more sophisticated way of measuring your genioglossus muscle, were significantly impaired. An interesting aside is that even when the train of four returned to 100%, so normally we'd say this is great, two out of 12 of these volunteers still had impairment.

And I wanted to just mention that, you know, we we do train a four in part because it's been studied and in part because it's convenient. But uh it you have to have eighty percent of your acetylcholine receptors blocked before you see the first decrease in train of floor ratio. So I think it's important to keep in mind that it's really just looking at one small range across a much larger spectrum of neuromuscular blockade, we just happen to be blind until we have enough blocked that we start to see a decrease in train of four ratio. Got it. So two key takeaways First, our measuring techniques may not have the fidelity to give us information across the larger spectrum.

And second, it seems like based on these studies on the upper airway the consensus for train of four targets increased from 0.7 to 0.9. Yeah, I think it was these studies in addition to a number of others. The idea was that maybe it's more than just those spirometry values uh looking at things like the upper airway patency led to a big push to increase what we called acceptable reversal of neuromuscular blockade. And it looks like all of this was in relatively healthy volunteers. So what do we have in terms of evidence of the impact of residual blockade in, for example, the PACU?

So there's a study in 2012 by Kumar uh called Residual Neuromuscular Blockade Affects Postoperative Pulmonary Function. And interesting, this is this study showed some uh differences from the original Ali trials in that they looked at uh preoperative spirometry values and compared them to pacchy spirometry values in patients with uh residual neuromuscular blockade. So the design was they had 150 ASA 1 to 2 patients who all had preoperative spirometry And they looked at FVC, uh force vital capacity and peak expiratory flow rate, and they quantified the percent change from preoperative values. And they compared groups who had train-of-four ratios of less than 0.9 versus train of four ratios who had greater than 0.9 at the time of the PFTs.

This was sort of a wild, in the wild type study, in that they left the reversal to the judgment of the clinician What that meant practically was that in the PACU, 57 % on initial measuring had residual neuromuscular blockades, so over half of them. And they now obviously all the people when they first showed up in the packet you couldn't have their spirometry done because they couldn't participate. Uh they were still under the effects of anesthesia. So they waited until they could participate and then they did the PFTs. At that point, 26% had residual neuromuscular blockade.

And of that group, the average train to four ratio was 0.7. Some uh standard deviations there of about 0.14 What they found was that the FVC was 13% lower than their pre-operative value, and that the peak expiratory flow rate was 9% lower. than the pre-operative value. So this is a little bit different than Ali 's 1975 study because it actually showed some difference from pre-op in these spirometry values. So that's statistically significant, but how do we think about that in terms of clinical relevance, uh, especially when we think about things like traditional pulmonary risk scores? It's a really good question because the decrease in FVC was only 13% and PA PEFR was only 9%.

And in different settings, like in chronic lung disease and so forth, physicians usually only make uh hay out of something over 15%. So these decreases, especially if we consider them to be transient, may not be that clinically significant. So it's a really good point. An astute question that was raised by one of our colleagues, Dr. Spiro, was whether effort might have played a role Considering that FVC and PFR are both flow-dependent metrics. Yeah, I think it's a it's a great point.

Less effort because of the post-anesthetic state could be at play here Dan, you had mentioned something about the attenuation of the ventilatory response to hypoxemia. What's that all about? Yeah, so the idea there is that the carotid body chemoreceptor uh might be less sensitive to hypoxemia if uh acetylcholine receptors are blocked. And there's some plausibility there from animal models. So one of the questions that folks have put forth is if you still have residual neuromuscular blockade, is your ventilatory response to hypotoxemia going to be attenuated?

So we have a couple of studies that have looked at that So in uh this first study, it's called Attenuated Ventilatory Response to Hypoxemia at Vecuronium Induced Partial Neuromuscular Blockade. I believe this is by uh Ericsson's group They had uh 11 healthy volunteers. What they did here in the group that's most relevant to what we're talking about, the hypoxemia group, was they made the patients hypoxemic hypoxemic. And they they compared control to uh residual neuromuscular blockade. And the way that they made them hypoxemic was giving them an FIO2 of of ten to twelve percent, low FIO2s.

They titrated their SPO2, I think, to 84 %. And in the control group, when they had that low of a uh of an FIO2, that low of a pulse of a of a pulse oximetry. Their respiratory rates and tidal volumes were increased, this is in the control group, not paralyzed, and their minute ventilation increased from 9.2 to 10.8 liters per minute. In the folks who were also exposed to hypoxemic but were with residual neuromuscular blockade, their train to four ratios were 0.7 There was no increase in title volume. There was a little increase in respiratory rate such that the minute ventilation response uh did go up, but it was only 50% of what they saw in the control folks who had no paralysis So the idea here, at least suggested by this small study in 11 Healthy Volunteers, was that paralytic can attenuate your ventilatory response to hypoxemia I see.

So when compared to the control group, at a train of four ratio of 0.7, the volunteers appear to have a depressed response to hypoxemia. This study was also recreated fairly recently, right? So yeah, it was recreated. There's a study in 2019 by Brohn's B R O E-N-S. It's called reversal of partial neuromuscular block and the ventilatory response to hypoxia.

They had 40 healthy volunteers who were all put on rocuronium infusions with a trainophore target of 0.7. Uh this was looking both at the attenuation of response to hypoxemia, but also at differences between neostigmine and to gamidex reversal and so forth in terms of the reversal of that. I'll ignore those parts of the study. What they did find though was that a train of four ratio of 0.7, the hypoxic response was blunted by 42%, which is exactly what we saw in the last study. What was particularly interesting though was that even after reversal of train of four to 100%, so to a a a train of four ratio of 100%, the hypoxic response was still blunted.

It wasn't back to 100%. It was 86% of baseline. And that was statistically significant between the two groups. Very interesting. So does that mean that there's a chance that the range we're observing isn't sufficient to capture all the discernible effects?

Absolutely, I think that's exactly what it means. Whether all those effects are clinically relevant is a different story, but I think it has to do again with the fact that if we're just using train-of-four ratio We're blind until that that last twitch heart height starts to decrease, which takes a lot of acetylcholine receptors being blocked. Now, do we have anything looking at train of four ratios and clinical signs and symptoms? Yeah, and I think that's a really good thing to look at because uh that's actually we'll find uh something that can be a big issue for patients' quality of recovery. In the study we just talked about, where they took 40 healthy volunteers, when they gave them some paralysis, train of 4 of 0.7, 80% of them had diplopia, 40% had difficulty swallowing, 40% had tosis.

So, in terms of signs and symptoms, this is a study from 1997 called Relationship of the Train-of-Four Ratio, Train-of-Four Fade Ratio to Clinical Signs and Symptoms of Residual Paralysis in Awake Volunteers. So it's 10 healthy volunteers. They gave Mivicurium bolus followed by an infusion. And they followed the train-of-four-ratio to see what correlated with different signs and symptoms. In terms of headlift and leg lift, both of those came back relatively early, train-of-4 ratios of 0.62 and 0.59 The bite actually took a little while longer to come back.

What they did was they put a popsicle stick in the patient's mouth and they asked them to bite down and hold it. uh the subject's mouths. And if the investigator could not pull the popsicle stick out, then it was considered adequate bite. In order to receive an adequate bite, the train of four ratio on average was 0.86 So it took a little bit longer to get those. Now those aside, all of the subjects had decreased grip strength. It was 83% of their control strength at a train of fur ratio of 0.9 They all had difficulty drinking through a straw, mostly because they couldn't create a seal around the straw.

They all felt generalized fatigue. And remember, all they're receiving is paralytic. And 100% of them had diplopia and difficulty tracking. A really interesting finding is that even when their train-in-floor ratio is back to 100% , Seven out of ten of them still had difficulty tracking in diplopia. And those participants needed an additional 45 to 90 minutes until their vision normalized So it sort of speaks to again, uh we're just looking at one small area on a very large range.

So it sounds to me like the next time I have trouble finding a quantitative train of four monitor I should use the popsicle stick test for neuromuscular blockade monitoring. You know, it's a good point, because on average if you were to extrapolate this data Your 204 ratio, if they could bite down and hold it, would be 0.86. That said, it's only 10 patients, it's healthy volunteers. I don't know how strong the ability to extrapolate is, but something to keep in mind. One additional sign, sure.

And Dan, I know you have one more study that has that evaluates some more subjective signs, right? That's right. So this was published in 2008. It's called intraoperative acceleryography monitoring reduces the risk of residual neuromuscular blockade and adverse respiratory events in the Pacio. So this was 185 patients and they were actually randomized to quantitative or qualitative monitoring In the excellent myography group, the one that got the quantitative monitoring, the degree of neuromuscular bloodcade was monitored with a top watch.

And in the quote-unquote conventional group, it was standard qualitative monitoring. Not surprisingly, train of four ratios were higher in the group that got quantitative monitoring, 0.98 versus 0.88 That was a significant difference. And the quantitative group had less residual neuromuscular blockade, defined as less than 0.9. The rates in the quantitative group were 14.5%, and in the one that had only qualitative was 50%. That was also significantly different.

So what they measured in this group were blinded objective assessments of strength, both in terms of objective measures, could they could they do certain tasks but also in terms of subjective, how difficult were the tasks to do. There were many measures and those were their primary outcomes. Subjective weakness was lower in the group that got quantitative monitoring. Wasn't hugely lower uh uh an average of uh four versus six, but it was statistically significant. And they had fewer symptoms, two versus five.

There was no difference in the signs. So in terms of objective measures, no statistical difference. Now importantly it was a pretty skewed deviation because the medians in both group were zero. In other words, all of the people in both groups could do, not all, sorry, the median uh in both groups could uh do the uh the physical task without an issue. So it may have been that with a larger sample we'd actually see a difference.

Another thing that they looked at here, David, and I think this is particularly important, because it's a different dimension of of effects of residual and neuromuscular blockade. They did what they called a global quality of recovery score, which was a visual analog scale, uh 1 to 100. And they found that the quality of recovery was higher in the group that was randomized to received acceleromyography. 85 versus 70. And that was statistically significant. And one could argue that a difference of 15 on a 100-point scale would also be clinically significant.

I don't know exactly what led to that. But it could be those things like less diplopia, less generalized fatigue, things that we've seen in previous studies carrying over to this bigger study. Does that make sense? Yeah, definitely. And from a stance to reason perspective, I could see how waking up from anesthesia and having problems with tracking or drinking from a straw might affect my perception of recovery.

Yeah. And and the other thing I want to point out too, it's not like the folks in this study who had qualitative monit monitoring had really low train to four ratios. Right? The average train of four ratio in in that conventional group was point eight eight, uh which is far from that point seven, uh that were initially in sort of standard of care guidelines Right. So even at these levels we're seeing some difference and and point eight eight is almost to the point nine metric that we commonly hear cited.

That's right. So to summarize what we've covered, it seems like we have some process studies suggesting some respiratory and clinical issues, but we haven't yet taken a look at any big outcome data. So I guess this is what you would call stance to reason stuff. What do we have in terms of outcomes? That's a really good question.

Because really all we have is sort of some of the, like you said, the processed stuff around spirometry or pharyngeal tone, a little bit of outcome data maybe around symptoms. But we do have some some studies that have looked at outcomes that might be more clinically impactful, either for patients or for systems. So one study that we'll look at right now looked at packy length of stay as a as an outcome measure. This was actually done at MGH. It was called uh posto-operative residual curization from intermediate acting neuromuscular blocking agents delays recovery room discharge This was done by uh Butterly and colleagues.

They looked at 248 PACU patients, and their primary outcome was PACU length of stay. comparing folks who had train to four ratios greater than 0.9 versus less than 0.9. Importantly, these were measured in the PACU and this was an observational trial. So there's this is just association data. This is not randomized. Of all of the patients that came through into the PACU, 22% had residual neuromuscular blockade defined as a train-of-4 ratio of less than 0.9 Now most of that group was in the 0.7 to 0.9 range.

In fact, the interquartile range was 0.7 to 0.9. So again, we're not talking about tremendously paralyzed patients. Now that said, the group that had a train of four ratio of less than point nine had an 80-minute longer PACU length of stay. They also looked at um time to uh uh appropriate discharge criteria from PACU, not just when they left the PACU, and that was also longer. So it seems, at least in this study, there's an association between train-of-four ratios and PACU length of stay.

They also did a kind of neat cueing analysis where they they looked at, you know, if we had 0% residual neuromuscular blockade, how many PACU holds would we experience versus If we if everyone had residual neuromuscular blockade, how many pacu holds would we experience? And uh the answer was about half of our patients would have PACU holds of at least a minute. if there were no residual neuromuscular blockade versus nearly all patients would have PACU holds if uh if we were closer to 100% of uh residual neuromuscular blockade. So this is a super interesting study to me because this seems to to suggest yet another dimension, this time systems level, in terms of implications of residual blockade.

Yeah, yeah, I completely agree. One of the inherent difficulties in studying rare events is that sometimes the population that needs to be studied needs to be really massive to be able to detect differences. And I think that's the advantage of this next study, which is a case control design. Right. And what a case control design is they they look uh in this particular instance they're looking for somebody who has the event of interest And then they find someone else who looks a lot like that person but didn't have the event of interest.

And they say, what's the difference between these two in terms of what we think is causing an issue? So I'll get a little more specific. This is from 2008, published in Anesthesia and Analgesia. This is called the study is called Residual Neuromuscular Blockade and Critical Respiratory Events in the Post Anesthesia Care Unit. And this study is by Murphy and colleagues.

So in terms of cases, they defined a case as any patient who had a quote-unquote critical respiratory event within the first 15 minutes of being in the PACU. What was a critical respiratory event? So obstruction, hypoxia, respiratory distress, inability to breathe deeply, and other symptoms, and then also suspicion of aspiration by the PACU nurse. So if the PACU nurse had these concerns, they would call one of the investigators over who would then confirm, yes, I think that this is a this is a critical respiratory event, and then they would measure the train-to-four ratio. Concurrently, they would identify someone else who's matched for sex, type of procedure, age, and so forth.

And look at wait for them to come to the PACU and then assuming that they had no critical respiratory event they would also measure their train of four ratio. So what they're doing then is comparing those two groups, the ones that had the events versus those that didn't, and they wanted to see is there a difference in terms of train of four ratios. So 7,500 patients later, they identified 61 critical respiratory events. Most of them were hypoxia or obstruction. So it's not a high rate.

These are rare outcomes They were able to match 42 with controls. So we're going to compare those 42 to their matched controls. Folks who had critical respiratory events had train of 4 ratios of 0.62 on average, plus or minus 0.2. So that's pretty low train-of-four ratio. Compare that with the control, the matched controls, the train-of-4 ratios on average were 0.98. plus or minus 0.07 and that was a statistically significant difference.

What I'll also mention is that they calculated odds ratio for obstruction, severe hypoxia, and any hypoxia, if your train of four ratio was less than 0.9. And and they calculated the odds for those were all in the three to six range for this small study. So it sounds like when they looked at these patients with critical respiratory events, there was a high incidence of residual blockade. something which was not seen in the control patients who didn't have any critical respiratory events. Yeah, I think that's well put. For the patients who had critical respiratory events. only 9.5 % of them had train or four ratios greater than 0.9, whereas in the control group, 90.5 % of them had train or four ratios greater than 0.9 Again, this is association data, but it's it's it fits with a lot of the stands to reason stuff that we've been looking at so far, so far.

Fair enough. So let's dive now into a trial that generated a lot of discussion and perhaps is aptly abbreviated as the popular trial. Right, so this is the post-anesthesia pulmonary complications after use of muscle relaxance, or the uh acronym there, popular trial. It's a multi-center prospective observational study. So this was 211 hospitals in 28 countries, and it's a prospective observational study, and they ended up looking at over 22,000 patients.

Their primary outcome was postoperative pulmonary complications, respiratory failure, infections, infiltrates, atelectasis, aspiration, bronchospasm, pulmonary edema. And not immediately, not just immediately, but from the operation through hospital discharge or post-operative day 28. So for what we're concerning ourselves with, which is what the actual train of four ratio was, we'll look at just the group that had quantitative monitoring. So of the 22,000 patients or so, it's around 4,000 patients. So we'll look at just those 4,000 patients.

Now, David, if if everything that we're saying so far stands to reason, well then we'd expect that people who had trained a four ratios of greater than 0.9 should have more pulmonary complications than those who had trained four ratios less than point nine, right? Yep. That's what we would expect So here you go. Folks who had trained four ratios of greater than 0.9 had a 10% incidence of those complications. And if you had some residual neuromuscular blockade, instead of 10%, it was 11.7%.

But the difference was not significantly different. There was no statistical significance. between those two in this observational sty in this observational trial. They did point out that any re receivable of any uh neuromuscular blockade did confer a higher uh post-operative pulmonary complication rate. It was eight point six versus three point three and that was statistically significant. Interesting, huh?

Very interesting and definitely counterintuitive based on what we've discussed up to this point. Do the authors make any hypotheses to try to explain the results? You know, there there are a number, and they looked at a much bigger window than post-operative window than we've seen other trials look at, but it you could argue that's a more clinically relevant window. Uh it's hard to say exactly what might have led to the difference. One of the thoughts that was uh offered was that maybe the cutoff Wasn't the right cutoff.

In this trial, most of them were using acceleromyography as opposed to EMG or MMG And acceleromyography tends to measure a bit higher than EMG. So they actually did a reanalysis that was published later uh where they looked at uh different top cutoffs and they said had we assigned a top cutoff of these different values would we have seen a difference in postoperative pulmonary complication rates Now importantly, this is all post hoc analysis, so it's not exactly what they were looking in for, so you you could worry a little bit about is this is this fishing That said, if you take a look at the actual paper, they see as the train of four ratio was higher, there there ended up being a high a bigger and bigger split between the two groups.

Uh what they found in this new analysis, and they looked at train and four cutoffs between 0.86 and 0.96 with the goal of finding what the most predictive cutoff was. And they found that if they would have set a cutoff of train four ratio of 0.95, it would have been associated with a statistically significant reduction in postoperative pulmonary complications. of 3.5%. 3.5% risk reduction. In that group, pack you length of stay would have also been shorter by about 10 minutes. So I think the contrast between the stance to reason studies and the outcomes of the popular trial is very thought provoking and I think it really provides an opportunity for listeners to critically appraise the evidence for themselves.

In particular, I highly recommend at least reviewing the discussion portion of the popular trial paper the authors do a really good job of trying to cover all their bases and at least discussing some of the possibilities with respect to their findings. Dan, can you summarize some of the evidence we've discussed in today's episode? Absolutely. So we looked at a mix of observational trials and uh especially the larger ones, which were all observational. versus some of the smaller trials which were randomized, which would set up sort of the plausibility of what we might see for association in the bigger trials. We looked at pharyngeal and esophageal tone, we looked at spirometry, we looked at attenuation of hypoxtemic respiratory drive, PACU -length of stay, and respiratory events.

And in terms of a different dimension, we also looked at symptoms that patients might experience. So here again are two questions from the start of the show for our listeners to think about. What is the level of your agreement with the claim that a quantitative train of four ratio greater than 90% is important to achieve prior to extubation? And what is the level of evidence for what you believe? Dan, thank you so much for joining us on the show today.

It's been an absolute pleasure. David, it's it was absolutely my pleasure to be here. To our listeners, thanks for joining us on the show today. If you enjoyed this episode, please leave us a five-star rating and review on Apple Podcasts. It helps other listeners to find our show.

I hope you've all had a restful Labor Day weekend and we'll see you next time. Stay hungry and keep asking questions.