SCCMPod-568 CCM: Neuromuscular Blockade in Adults With ARDS

Dr. McLaughlin: Hello and welcome to the Society of Critical Care Medicine podcast. I'm your host Diane McLaughlin. Today I'm speaking with Dr. Aarti Sarwal and Brian Erstad, a pharmacist and MCCM about the article SCCM Guidelines for the Administration of Neuromuscular Blockade in Adults with Acute Respiratory Distress Syndrome, published Critical Care Medicine. To access the full article, visit ccmjournal.org. Dr. Sarwal is a professor of neurology and the Division Chair of Neurocritical Care at Virginia Commonwealth University School of Medicine in Richmond, Virginia. She's also the Associate Editor of Critical Care Medicine, Secretary of the American Society of Neuroimaging, and Director of VCU Wake Forest Neuroultrasound Courses.

Dr. Erstad is a tenured professor and Interim Dean at the University of Arizona R. Ken Coit College of Pharmacy. He is also a Center Investigator for the Center for Health Outcomes, a member of the Bio 5 Institute and Comprehensive Center for Pain and Addiction, and Pharmaco Economics Research Center, and a Co-Director for the Arizona Clinical and Translational Research Graduate Certificate Program.

Welcome. Before we start, do you guys have any disclosures to report?

Dr. Erstad: No disclosures.

Dr. Sarwal: None related to the guidelines.

Dr. McLaughlin: All right, excellent. So we're going to jump right into what this guideline’s about. For listeners who don't utilize paralytics frequently, can you briefly explain the physiologic rationale for neuromuscular blockade in ARDS?

Maybe we'll start with you, Dr. Erstad, as our pharmacist on board.

Dr. Erstad: Well, the classic things that are always mentioned are to decrease volume and pressure trauma and reduce asynchrony. Those are the ones that you'll often hear about. But to me, there's a couple of more interesting things, and we'll get into this when we talk about two large trials that have been conducted.

But one of those trials that led to the ACURASYS trial actually looked at cytokines and how basically we had an attenuation of inflammatory mediators, and that study was done with cisatracurium. So that was another potentially unique mechanism that hadn't really been brought up in the past. And then one, to me, that I rarely see mentioned in the literature, but I can't help but wonder if it plays a role, especially for continuous infusions, is the issue of allowing the lungs to rest and recover, sort of analogous to ECMO.

And that's just something, again, I don't see a lot in the literature, but I have to wonder, could that possibly explain differences between, for instance, intermittent versus continuous infusions? But those are some of the classic mechanisms that are brought up.

Dr. McLaughlin: So, knowing that many people already utilize paralytics in ARDS, Dr. Sarwal, what do these guidelines add to the previous existing guidelines, particularly the ones that were released around the time of COVID?

Dr. Sarwal: And Diane, that's a great question. In following up the previous reported guidelines by other professional organizations and the evolving literature on this topic, our focus on choosing these PICO questions was really to hone down where is the evidence aligned with regards to the certainty of the evidence and the robustness of the rigor of the clinical evidence that supports neuromuscular blockers in ARDS and isolate where the best, which subset of patients, which phenotype of ARDS or which state of ARDS does the evidence most point to the utility of these agents. And our effort regarding isolating this subset and looming down the evidence was basically to provide an introspective call for researchers, for clinicians to basically highlight the research gaps and the clinical gaps that exist.

The field has seen so much work in the last two decades, but there is still so much more to be done. So our hope was that the first PICO questions of addressing the indication that neuromuscular blockage narrows down the population where the evidence best support and provides the emerging areas in which we think more research can lead to better interventions to improve outcomes in ARDS.

Dr. McLaughlin: So before we go into what the guidelines actually say, you both have referenced the evidence. So maybe let's talk about these two trials that are a big part of what has shaped the new guidelines. So many clinicians were influenced by the ACURASYS trial.

Dr. Erstad, could you briefly summarize its key findings for us?

Dr. Erstad: Yeah, there's two major trials, ACURASYS and ROSE-PETAL. And the ACURASYS trial had a primary endpoint. It was a hazard ratio for 19B mortality, and it was significant. And I should point out that this was, again, using a continuous infusion, high dose continuous infusion of cisatracurium for 48 hours. And I do mean a very high dose, which you might want to follow up what I mean by that. But basically they found that for the hazard ratio, it was a 0.68 with a 95% confidence interval of 0.48 to 0.98. And the crude 90-day mortality was also at P equals 0.05. And so this was, again, a multicenter trial conducted in France, large number of patients, 339 patients with PF ratios less than 150 and on a peak of at least five. And it definitely created a pause for all of us when we saw that trial come out.

Dr. McLaughlin: Well, now I have to ask, what was the dose?

Dr. Erstad: Actually, I'll provide the background for this dose because it was a 15 milligram bolus followed by a dose of 37.5 milligrams per hour, continuous infusion for 48 hours. That is a large dose for people who weren't used to getting those kinds of doses. And the way they came up with it, I've mentioned before, there was actually a series of trials leading up to ACURASYS, at least three trials leading up to that by your French investigators. And actually in a couple of those trials, that's what they were trying to do is come up with a dose where they can maintain blinding of the study, allow for blinding of the study, which meant they had to have a high enough dose so that you have basically no use for train of four monitoring. And so what they had done is they looked at all their previous studies had been done and basically picked a dose that pretty much would make for a zero out of four, train of four for pretty much every patient. And then that's how they arrived at the dose. And then that allowed them to not use train of four monitoring because they basically knew they were suppressing in all of the patients.

And so that's again, something that critical care physicians, it gave us pause because we're used to having train of four monitoring. I think it's quite common that we do it, even though in this case, again, they purposely didn't do it to maintain blinding.

Dr. McLaughlin: I'll say from a nursing standpoint, that's definitely unusual. You know, we love to play with our train of four. So after ACURASYS, then ROSE-PETAL came next, which again shifted the narrative.

Dr. Sarwal, what were the most important differences between ACURASYS and ROSE-PETAL?

Dr. Sarwal: ACURASYS basically tried to answer the question whether early time limited paralysis and moderate to severe ARDS under deep sedation impacts outcomes. ROSE-PETAL basically shifted that to show the evolution of ARDS care during the time as it was done quite a few years later. And that tried to answer the question, does early paralysis improve outcomes compared with a modern live sedation strategy.

So ACURASYS had deep sedation, but by that time, more and more light sedation was being used. So that's what ROSE tried to address. From the outcome perspective, the mortality signal was, of course, the most surprising finding. That's why it was halted early. ACURASYS reduced 90-day mortality with a hazard ratio that favored neuromuscular blockage. But ROSE did not show any difference in 90-day mortality.

So ROSE basically neutralized the prior mortality signal that we had seen from ACURASYS. From the ventilator strategy perspective and PEEP perspective, there were significant differences. So if you look at ACURASYS at that time, lower PEEP strategies were pretty common. This was pre-high PEEP awareness. And by the time ROSE came in, high PEEP strategies were pretty acknowledged in ARDS protocols. So that was significant difference with regards to PEEP instituted. ROSE had a little bit of a higher baseline lung protective optimization that patients were optimized on ventilator strategies. They were optimized on sedation prior to the initiation of neuromuscular blockade compared to just early institution of neuromuscular blockade in ACURASYS. So that could have reduced the incremental benefit that neuromuscular blockage could have otherwise produced.

And then prone positioning was another evolutionary change in ARDS. There was much higher proning happening by the time ROSE was done. It was more contemporary ARDS care and it was kind of more adjunct ARDS optimization, which kind of minimized the role of neuromuscular blockage.

So we wonder whether this more optimization of other alternative strategies took that difference in benefit away. Lastly, the adverse events were much higher in those in the neuromuscular blockade arm with regards to cardiovascular events and ACURASYS had not shown such events. And I think ACURASYS had not shown excess weakness.

It was, of course, terminated early, but the evolution of the ARDS strategies, optimization of the adjunct ARDS strategies before initiation of neuromuscular blockade, higher peak strategies, and of course, all mitigating the mortality benefit are probably the biggest difference that was pivoted on the understanding of ARDS.

Dr. Erstad: To add to what Aarti said, and to put this in perspective, the two studies were almost 10 years to the month apart from each other. So we're talking a decade. And so besides all of those differences between the studies that Aarti mentioned, you just wonder what about all of the other changes in practice that we're not even considering?

You know, it's sort of this analogy with randomized controlled trials versus observational, whereas randomized trials, not only are you randomizing the confounders, but you're randomizing unknown confounders, and that's the advantage to randomization. And so here, that analogy is what are the unknown things that might've occurred over that decade, changes in practice, et cetera, that could have led to those differences. Again, so a decade’s quite a long time between those two trials.

Dr. McLaughlin: And we all know quite a bit has happened in between those trials. But now that we have this landscape for the evidence that's changed, how did you guys come up with recommendations regarding continuous neuromuscular blockade in moderate to severe ARDS?

Dr. Erstad: What we should do at this point is for the listeners just to tell them what the actual recommendation was. And basically, we're suggesting using the neuromuscular blockers but we're not using those in adults with ARDS, if they have a PF ratio of less than 150, and if they're persistently hypoxemic and not achieving metacavical ventilation targets on sedation. And then as for the strategy, which is our second recommendation, we suggest either a fixed-dose strategy without monitoring depth of neuromuscular blockade or a titration-based strategy by monitoring depth of neuromuscular blockade for adults with ARDS.

And I point out that these recommendations, all five of our PICO recommendations related to the PICO questions were all conditional recommendations because all of the evidence was low or very low quality of evidence.

Dr. McLaughlin: Can you talk a little bit about what exactly people should do with a conditional recommendation? Because, you know, you open a guideline, you expect it to tell you, hey, this is your patient, this is what you should do. What do you do when the recommendation's conditional?

Dr. Sarwal: I think that's a great point. And this is where the strength of following a methodological framework like GRADE is very valuable. And the guidelines do provide a framework for people reading these documents on how the strong recommendation versus conditional recommendation can be received with regards to the actual patients.

The conditional recommendations essentially represent a recommendation where a majority of the individuals in a very given classical situation without any nuances would go on to suggest a recommendation and it would apply to most people in a simple scenario addressing that question. But the place where it differs from the strong recommendation is that a significant minority of patient with nuances where the actual evidence may not apply. It allows clinicians judgment to exercise their interpretation of the literature, their interpretation of the patient's characteristics that allow you to deviate.

So strong recommendation will denote that nearly all individuals in a given situation would do what the recommendation is asking you to do. But conditional recommendations allow you to accept the humility of the lack of very strong evidence and allows you to have nuances and patient-specific context to be figured when you're altering your decision from what the recommendation is otherwise pointing towards. So I think it gives clinicians a little degree of freedom to exercise their clinical judgment because you expect clinicians to spend more time taking into account patient circumstances, preferences, values, shared decision-making, multidisciplinary collaboration. So it allows you the leeway to put those contexts in picture when deviating to what otherwise would seem like a simple recommendation based on the deadline.

Dr. Erstad: Yeah, I think then for what Aarti's saying, and I wholeheartedly agree with that, that I think that often people, they want a black and white, you know, answer, here's what you do. But the more we learn, especially about ARDS, we know there are different phenotypes. And I suspect as that literature continues to come out, we'll get better at deciding which of these regimens and which patients we should use. But right now, we don't know. Again, what we know is that there are definitely these different subsets of patients. But I think right now we're sort of at the point where we just have to make those decisions based on that individual patient at hand and the best literature we have available.

I will say that, just for background, you might find this interesting because I gave a presentation at SCCM shortly after ACURASYS had come out and way before seeing ROSE-PETAL. And I asked people, I provided the dosing regimen on a slide and basically asked for a show of hands, how many of you would be willing to do this?

Now you've got a study that's shown to decrease mortality by using these very high doses, continuous infusion for 48 hours. And there were very few hands in that audience that went up. And I venture to say, I think that's still the case regardless of ROSE-PETAL.

The idea of giving just very high doses for 48 hours, continuous infusion, no breaks, is, for lack of a better word, just scary to a lot of physicians. But the flip side is for those if you really believe in evidence, like right after the time when that came out, obviously you want to mimic the trial as much as possible to get the results. And so one of the issues comes up, well, can we, for instance, give it for a shorter period of time?

And when I hear those kinds of things, you know, so again, even before we knew ROSE-PETAL, my response to that would be, yeah, but the trial did it, high dose for 48 hours. And so we don't know what it means if you give a lower dose or if you give it for 24 hours. So again, I know it can be frustrating for clinicians, but it does come back to that, I think that individual patient decision-making process.

Dr. McLaughlin: But you do bring up an interesting point about outcomes and what outcomes you were looking at as a panel when evaluating the evidence available. First, you mentioned mortality, I think that's the big thing everybody looks at. In your PICO questions, was that the primary outcome?

Dr. Erstad: Yeah, we actually looked at various forms of mortality. We looked at 28-day mortality. We looked at 90-day mortality, ICU mortality, you know, length of stay, ventilator-free days, a variety of these endpoints. We looked to see if the evidence varied depending on which of those parameters you're looking at, and probably more details than we need for the purposes of this. But just suffice to say, we did look at a variety of what I'd consider to be clinically important endpoints.

Dr. McLaughlin: And then in terms of, because I agree with what you said earlier, that's a hefty dose that would give you pause before just ordering. Did you look at some of the secondary outcomes like length of stay, ICU-acquired weakness? Dr. Sarwal, can you talk about some of the complications of utilizing continuous neuromuscular blockade?

Dr. Sarwal: Then we did look at lots of secondary outcomes that could represent physiological benefits of neuromuscular blockade, things like barotrauma, oxygenation, ICU length of stay, as well as ICU-acquired weakness, which is one of the most feared complications, especially with high-dose neuromuscular blockade. And with barotrauma, we found decreased risk, but it was considered a favorable physiological signal. Of course, there was significant trans-neutrogenity in the evidence we found.

With regards to oxygenation, ACURASYS was a major determinant in the signal of early improvement in oxygenation, but this was not consistently linked to patient-centered outcomes. ICU length of stay, we did not find significant reduction. We found very high confidence intervals, so we actually had to downgrade the evidence for imprecision.

And then ICU-acquired weakness, we acknowledged the fear. Evidence does give signals of increased risk, slightly so, but the confidence interval did cross one, and this did contribute to the caution and made us with a conditional recommendation of keeping that outcome in mind with patient-specific choices. So all these secondary outcomes did inform the strength of our recommendations and the remarks that we provided as a part of each question being included in this guideline.

Dr. Erstad: I would also say that it's important to note that when it comes to the adverse effects, that both the ACURASYS and ROSE-PETAL, you know, there were certain types of patients that were excluded in that we just simply don't have good information on and that are potentially concerned when using neuromuscular blockers. And so, you know, the idea of patient with neuromuscular blocking, with neuromuscular diseases, as an example, you know, patients depend, again, this wouldn't necessarily apply to cisatracurium, but for other neuromuscular blocking agents, how are they eliminated? Kidney, liver, do we have dysfunction of those organ systems that could affect the agent?

Do they have active metabolites? And then also for adverse effect concerns with neuromuscular blockers, it's not the ones you classically think of as just due to the drug, but also what about things like inadequate sedation with it, where you could have a person because of inadequate sedation, have awareness, potentially be pulling lines. And so, you know, often we think of drug adverse effects that are really specific to the drug, but in this case, it's meeting, you know, other things that you need to have associated with it that can also cause problems in disconnection from ventilator, as an example, when you're on continuous neuromuscular blockade.

So those all, ultimately, would sort of need to be considered under the adverse effect profile.

Dr. McLaughlin: So you bring up a really, really important point, and I'm very glad that we have our neuro expert here. How do you approach sedation depth in these patients that you are initiating continuous paralysis?

Dr. Sarwal: That's a million-dollar question, and probably the healer for evidence right now, Diane, and thank you for putting the neurologist on spot. We toiled around this question with regards to whether we will tackle choice of monitoring strategy. Brian and I went around and down with the panel, and we really wanted to address that question.

Unfortunately, we did not find any good evidence of randomized controlled trial, just small comparison studies, both with regards to monitoring the depth of neuromuscular blockade and the depth of sedation and analgesia individually before initiating neuromuscular blocker, as well as during the maintenance of neuromuscular blocker. We toiled around neurophysiological monitoring, ranging from electroencephalography, cerebral oximetry, blood flow devices, diplometry-based devices that look at autonomic responses, quite a few exciting directions where this field is going with regards to monitoring the depth of sedation and analgesia. We also came back to the drawing board with regards to clinical assessment, and especially prior to initiating neuromuscular blockade, we recognized that there is some clinical value in looking at signs, but everybody may not have the skillset to apply heuristics to the pattern recognition.

You know, we all have worked with nurses and pharmacists that could go by the patient's bedside and say, I don't like this patient's heart rate. This patient needs better sedation. How much of that have inbuilt that heuristic into our day-to-day rounding and the level of detail that needs?

So I think we acknowledge clinical assessment. We acknowledge the lack of evidence around the best monitoring strategies with regard to depth of analgesia, and the urge towards continuing to include that as a PICO question, despite the lack of evidence, was the driving factor behind publishing them and continuing to proceed with the recommendation as an essential call to researchers and clinicians that this is an area that really needs significant emphasis. You know, all of us, we don't need an evidence-based trial to tell you that patient's level of comfort, patient's lack of recall from that traumatizing experience of being on neuromuscular blockade is a very important patient-centered outcome. But what's the best strategy to consistently obtain that across all our ARDS management strategies?

That's going to be the golden question for ARDS researchers going forward, and I hope that these guidelines trigger that curiosity and work towards that goal.

Dr. Erstad: And I will qualify or add to something that already said, that there's two very separate recommendations here, and this is, I think, source of controversy, apart even from the guidelines, with various clinicians, is the sedation strategy before they're put on neuromuscular blockade, if you're going to go to a continuous infusion of neuromuscular plate, and during. During, pretty much everybody agrees, well, at that point, you need to have adequate depth of sedation, analgesia, you need to make sure those are insured, but what happens before that? That's where there's controversy, because there's this group out there who, when they hear deep sedation, there's literature out there that suggests you get things like reverse triggering, double triggering of the ventilator, kinds of problems that, and by the way, associated with deep sedation, those kind of problems appear to have this association with deep sedation.

Maybe there's one group who are thinking, we really want to avoid deep sedation because we know it can lead to these kinds of ventilator asynchronies, but then there's actually even other guidelines out there that say, well, you shouldn't put a person on these continuous infusions until they've basically already failed deep sedation, and so you have, you know, again, that whole area of sedation strategy, as already mentioned, is really controversial up in the air, and unfortunately, it's not answerable by the current literature.

As a matter of fact, a recent study that just came out that was looking at prescribing patterns of these agents in a number of different centers, not surprisingly, found a good deal of variability. They found in general, there seemed to be guideline compliance, but there were some real concerns in certain centers in terms of what was being done.

Dr. McLaughlin: That's interesting, and it kind of goes with, from here, what are the next steps? And it sounds like there's still a lot of need for ongoing research.

Dr. Erstad: Yeah, we identified research priorities, and we actually have a listing of those, and again, there's more than even the ones we list.

Dr. McLaughlin: Knowing all of the uncertainty that still exists, and the recommendations that were able to be made, if you were to bring one point each forward about what the takeaway from these guidelines should be, what would it be?

Dr. Sarwal: I think, from my perspective, the biggest takeaway would be we have come very far with regards to understanding what harms our patients in ARDS, and the humility that this evidence brings us should inspire us to move forward with strategies that minimize harm to our patients. Do no harm is the basic practice of being a clinician in these settings, so this should be just a lightning call to researchers that, as far as we've come with ARDS, not just neuromuscular paralysis, but with regards to our other strategies, let's look at patient selection criteria with regards to degree of oxygenation, let's look at that from sparing strategies, let's look at ARDS phenotype-specific benefit, let's look at intersectionality of various ARDS therapies, you know, which patient subset benefits from a combination of proning and steroids versus proning and neuromuscular paralysis. I think with precision medicine coming into focus in critical care, this is a call for new technologies, new strategies to artificial intelligence for us to find more patient-specific interventions that minimize the harm that we do and hopefully improve outcomes.

I'm very thrilled to see some work already being done in that regard, but my real hope is that rather than being a frustrating lack of evidence, that this becomes an inspiration for folks to see that we have identified areas that need work, and this could be a call for researchers to focus on those research gaps within them.

Dr. Erstad: For me, from a practical standpoint, a personal standpoint, it doesn't reflect the panelists, my personal perspective, that if I'm admitted with ARDS to a hospital in the United States, I probably wouldn't want the high-dose continuous infusion for 48 hours, but if I'm traveling to France and happen to develop severe ARDS, you could probably go ahead and give me the high-dose continuous infusion because, again, not only the ACURASYS trial, but a couple of the trials leading up to it tended to show these consistent results with continuous infusion. Now, feel free to delete that part from the recording.

Dr. McLaughlin: Yeah, that's interesting.

Dr. Sarwal: No, I am actually very much looking forward to work that is being done in combining moderate sedation with partial neuromuscular blockage, and this whole concept of diaphragm sparing, you know, people know my bias towards preserving the diaphragm being a neurologist myself. It's my second most favorite muscle after the brain.

I love the direction that we're going in with regards to actually looking at ventilator dyssynchrony and truly quantifying that in a manner that is translatable across medicine, where people not just look at waveforms and depend upon my ability to interpret those waveforms, but a less expert, a more novice clinician can really get some index markers. I almost think of it like as an ICP monitor. I think I would love for the field to go where, just like I have an ICP monitor to look at serendipityma, there is a vent dyssynchrony monitor by the bedside, where the nurse could come and talk to the pharmacist and say, hey, this has crossed the threshold of 20 for more than 25 minutes, and I would like to have either more sedation or more neuromuscular blockade or bring the clinician to bedside and, you know, do ventilator strategies to minimize dyssynchrony by changing the vent modes and the vent parameters. So I'm very encouraged by the emerging focus of folks towards vent dyssynchrony, precision medicine, things like extracorporeal, CO2 removal, but more so than that, the diaphragm sparing ventilators and neuromuscular blockage strategy is I'm absolutely looking forward to.

Dr. Erstad: If I could add, I just feel like I really need to recognize our panel members as well. We had a couple of public members that provided fantastic input into the guidelines, and so a great international panel with a variety of disciplines, and again, including those two public members and just really invaluable input.

Dr. Sarwal: Definitely. I think we were lucky enough to get an intensive care physician that himself was a patient in his own unit with ARDS and could really provide the patient's perspective while debating their literature with us. So that was one of the most humbling experiences of being a part of this panel, and I can't thank him and his wife enough for giving us the honor of sharing that perspective with him first on.

Dr. McLaughlin: Well, so there you guys have it, hot off the presses, the 2026 update to the continuous neuromuscular blockade guidelines and ARDS, and maybe a sneak peek at the 2036. But in the meantime, this will conclude another episode of the Society of Critical Care Medicine podcast. If you're listening on your favorite podcast app and you like what you heard, consider rating and leaving a review.

For the Society of Critical Care Medicine podcast, I'm Diane McLaughlin.

Announcer: Diane C. McLaughlin, DNP, AGA, CNP, BC, CCRN, FCCM, is a neurocritical care nurse practitioner at University of Florida Health Jacksonville. She is active within SCCM, serving on both the APP resource and ultrasound committees, and is a social media ambassador for SCCM.

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