SCCM Resource Library-Dosing Strategies for Paralytics in ARDS: Keep It Steady or Time for a Change? Continuous/Flat-Dose Strategies

Video Transcription

Hello, my name is Brian Erstad, and welcome to this session titled Dosing Strategies for Paralytics in ARDS, Keep it Steady or Time for a Change.  And my portion of the session, I�m going to talk about continuous or flat dose strategies. For those of you that know me, you know that I don�t like dichotomies, and I think in  the case of how to dose, whether to use neuromuscular blocking agents and how to dose them, I think it does depend on the clinical context.  But for the purposes of this talk, I am going to really make it a dichotomy and basically go with the argument that you should use a continuous flat dose strategy.  I have nothing to disclose for this presentation. And my perspective, I�m going to go with the best evidence. That�s going to be my theme, not anecdotal information.  And you�ll see at the end of my talk that I�m going to repeat this, that the best evidence in terms of neuromuscular blocking agents in survival is when they�re used  by continuous infusion flat dose strategy. And again, the reason I�m avoiding anecdotal information is because we have higher level evidence available.  And we all know the problems when you try to use anecdotal evidence when we�re looking at any type of clinical question.  Here�s an example, an early attempt at mechanical ventilation. And anecdotally, this may seem like the way to go.  But if you look closely, I don�t think this is going to work very well. Last time I checked anatomically, the lungs aren�t in this position.  Well, I was fortunate to be a member of the latest neuromuscular blocking agent guideline committee that was headed by Dr. Michael Murray.  And I will point out that these guidelines were published in 2016. That�s important to note because a couple of the trials, key trials that I�m going  to talk about today were actually published after these guidelines.  So obviously, they could be taken into account in an update. But again, I want to refer to these guidelines as a starting point.  And to begin, I wanted to make sure that we�re all on the same page with regards to grade nomenclature which was used when compiling these guidelines.  And this is something for trainees, I always point out, you�ve got to be very careful when you look at the wording in terms of recommendations and guidelines.  And recommend, when that word is used, then that�s used for a strong recommendation. Suggest is used for a weak recommendation.  There are other things that we took into account in these guidelines that hadn�t been done in previous versions of the neuromuscular blocking agent guideline document such as  good practice statements where it�s really used with a strong recommendation when there�s really no clear alternative such as, you know, the need to use analgesia and sedation.  But again, what I really wanted to point out for this slide is the difference between recommend and suggest, recognizing suggest as a weak recommendation.  And so here at the time was our recommendation with regards to ARDS. We suggest that a neuromuscular blocking agent be administered by continuous IV infusion  early in the course of ARDS for patients with a PF ratio less than 150. And that was a weak recommendation based on moderate quality of evidence.  And that evidence was primarily coming from the ACQUIRISIS trial, which is one of the trials I�ll be talking about today.  Well, I wanted to begin by going through some of the trials, but I wanted to point out that there were a number of trials leading up to ACQUIRISIS and the ROSE PETAL trials.  And I think it�s important to take a look at some of these early trials because they did lead the way for those later trials.  And one of the first ones, and by the way, you�ll notice that there�s a series of studies that were conducted in France. The first was by a group of investigators in 2002.  It was a multicenter, randomized controlled trial. And they were looking at TRANF4 and using cis-atricurium and basically using cis-atricurium  either to maintain a TRANF4 of 0 of 4 twitches or 2 of 4. And you�ll look that the duration of paralysis is similar.  Medium recovery time was actually longer, and I don�t think this would surprise anyone when they were looking at a TRANF4 of 0 to 4.  And basically, if you look at their conclusions, the blockade to achieve a TRANF4 of 2 of 4  provided similar respiratory benefits as TRANF4 of 0 to 4, but with lower doses and shorter time to recovery of muscle strength.  And again, I don�t think that would probably surprise you that it would take lower doses when you�re going for a higher TRANF4.  But I bring this up because this was one of the first trials looking at cis-atricurium dosing strategies for ARDS, and it was conducted in France.  And as you�ll see in a minute, this was the first in a series of RCTs. Well, the next trial published a couple years later, another multicenter RCT conducted in France.  And in this case, 56 patients, and you�ll notice the PF ratio in this study. And again, pretty much all of these studies were using assist control ventilation with  tidal volumes of 6 to 8 mLs per kilogram based on what�s often referred to as a predicted weight, which is actually an ideal body weight.  And again, infusion of cis-atricurium, and this time for 48 hours. And the primary endpoint was looking at the PF ratios.  It was higher at all points in the cis-atricurium compared to the control group. It was first statistically higher at 48 hours, but then it remained higher through 120 hours.  And notice that in this early trial, there were trends towards decreased length of ICU stay and death using cis-atricurium for ARDS.  Then the next trial conducted in France by Pharrell, another multicenter RCT. But I�ll point out in this case, this was looking more at mechanistically what might  be happening with cis-atricurium. There�s been a variety of points made as to what could be the mechanism for neuromuscular  blockade, the benefits, if they�re assuming there are benefits in ARDS. There�s been explanations related to barotrauma and other explanations.  This one was focused on pro-inflammatory mediators and whether infusion of cis-atricurium would  in essence decrease some of these pro-inflammatory mediators that could be aggravating, causing ARDS.  And so, they were looking at these pro-inflammatory mediators both in the lung and in the serum.  And if you look for the primary endpoint, in terms of these pro-inflammatory mediators, the 48 hours, the interleukin serum levels were decreased in the cis-atricurium group  significantly so. And actually, they were also decreased in all of the pulmonary samples.  And so, basically, they did find this significantly higher PF ratio with lower PEEP over 120 hours  with cis-atricurium and, again, found reductions in these pro-inflammatory mediators. And there was only one patient in each group that had clinically detectable neuromyopathy  and each had received less than four doses of neuromuscular blocking agent after 48 hours of study period. I won�t talk a lot about neuromyopathies today. This is a concern.  It�s been an ongoing concern with neuromuscular blocking agents. But as you�ll see, it really didn�t appear in any of the randomized control studies that  was come or at least there were no significant differences between groups. And so, I�m really not going to say a lot more about it other than acknowledging that  it is an ongoing concern. And some would argue it�s a particular concern when you�re combining it with corticosteroid agents. But, again, that�s for another time.  And then the study, one of the studies that, again, has been most cited in this debate  as to whether to use continuous infusion cis-atricurium, and this was the so-called ACURISIS study by Papazian.  And it�s multicenter blinded RCT, again, in France, 339 patients that were ultimately enrolled.  But then there was one that couldn�t be, one patient wasn�t available for analysis. And again, PF ratios looking for less than 150 with a PEEP greater than 5.  As I said before, a cis-control of tidal volumes of 6 to 8 mLs per kilogram based on ideal body weight was otherwise pretty much standard procedures for support and weaning.  And they did detail these, by the way, in the study.  Here�s one of the issues that has been talked about is that the cis-atricurium was used in a large dose.  It was 15 mg bolus followed by a continuous flat dose infusion of 37.5 mg per hour for 48 hours. And I should mention, realize this dose was used on purpose.  It allowed for blinding. And it also, it was derived from these earlier studies that basically suggested that at this  dose pretty much no patient was going to have any twitches on a 0 to 4 train of 4. And so again, it was done on purpose and the idea that you wouldn�t have to do any train  of 4 monitoring. And realize train of 4 monitoring is controversial in and of itself. There�s a lot of ways to misinterpret findings, placement issues.  Again, there�s not high-level evidence for train of 4 and in the guidelines, we basically  recommend it as one part of a number of clinical strategies for evaluating neuroblastocerebral blockade.  But in this study, they just frankly wanted to get around it and so train of 4 wasn�t used. And in this case, the primary endpoint of this hazard ratio for 90-day mortality, it  did suggest a reduction in mortality with cis-atricurium. You can see the 0.68 and that 95% confidence interval was statistically significant.  And this had the adjustments you see there on the slide. The crude mortality, again, there was a trend here.  Ideally, in a study, both the crude and adjusted mortality would be significant. But in this case, we could argue and if you buy into trends that this was a trend.  And then the 28 mortality, the significance level P is 0.05. And so again, I�ll leave it up to the listener to decide about these 90-day crude mortality differences.  Well, there were some other endpoints that were looked at in the Papazian studies and again, you can read through some of these.  As I mentioned earlier, there wasn�t any significant differences in terms of some of the adverse effects that would be of concern.  So bottom line with this study, there appeared to be this survival benefit and without any increased adverse effects.  And so this trial, in particular, was serving as the basis for the Suggest Recommendation in the latest version of the Rheumuscular Blocking Agent Guidelines.  Well, there was a lot of discussion of these various studies and especially the QRISIS trial. And on this slide, I have listed some of the positives and negatives.  And you�ll notice I bolded one example after this trial had come out as, well, would this translate into other settings with different ventilation and weaning protocols, patients  with multiple comorbidities? In other words, back to something I said at the beginning of my talk, what about the context?  And then how would it apply in different populations, different settings? And so that, again, is one of the big issues that we really need to look at.  But as I said, I�m taking the argument that this was a well-done RCT and they did find this mortality benefit and so we�ll leave it at that for now as we discuss the next  slide that started to muddy the waters, or the next trial. But before I get to the Rose Petal Trial, I first want to point out that there was one  study that came out actually just as we�re finalizing the 2016 neuromuscular blocker guideline.  And this was a study that was, the article was in Chinese and it was using Vecuronium. And it also suggested a decrease in mortality with severe ARDS.  But in this case, it really didn�t change our ultimate suggest recommendation. So I just point out that it was mentioned, but it ultimately didn�t change our recommendation.  And then there was a trial that came out after the neuromuscular blocker guidelines. And in this case, it was a study looking at Cysatricurium versus Vecuronium.  And in this case, Cysatricurium actually was associated with decreased vent time and ICU length of stay. Now, this was an observational study, not an RCT.  But nevertheless, this sort of gave some evidence that, for using Cysatricurium and whether it�s due to a unique beneficial effect of Cysatricurium, exactly why that�s the case.  Assuming you believe the findings, I mean, that�s still up in the air. But there may well be differences between the neuromuscular blocking agents.  And I�ll point out that the best evidence to date is using the ACQUIRISIS trial that used Cysatricurium flat high-dose continuous infusion strategy.  All right, well, now the next trial that, as I said, muddied the water is the ROSE-PETAL clinical trial.  And in this case, again, patients with ARDS, PF ratio less than 150 and a PEEP of at least 8.  Again, the patients were randomized to a 48-hour infusion of Cysatricurium, pretty much the same type of high-dose infusion as in ACQUIRISIS or usual care.  But in this case, the usual care group had lighter sedation, and the trial wasn�t blinded. Trial was stopped for utility, and when they ultimately looked at mortality, there was  no difference between Cysatricurium and the usual care groups. You see the doses of neuromuscular blocking agents that were used, and there appeared  to be some more serious cardiovascular events in the Cysatricurium group 14 versus 2, and this was significant.  So there were a number of editorials and letters that tried to discuss possible reasons for the differences between ACQUIRISIS and ROSE-PETAL.  You see some of those listed on the slide. ACQUIRISIS had a smaller number of centers and was conducted in Europe and France.  ROSE-PETAL, large number of centers, patients conducted in the United States. There was more prone positioning in ACQUIRISIS versus ROSE.  ACQUIRISIS was double-blind, lower PEEP used in ACQUIRISIS. There was deep sedation in the control group. And then I have question marks by the adverse effects.  The line in here in particular that I want to focus on is the difference in sedation. This is one in particular that I think is important to note, and you�ll see why in a minute.  The fact that ACQUIRISIS had deep sedation in the control group and ROSE-PETAL had this light sedation, so different sedation strategies.  And let me start by pointing out that after the ROSE-PETAL trial, there was this intensive care medicine, so-called rapid practice guideline.  And you�ll see, and this was published, I�ll point out, in 2020, so about four years after the guideline I was involved with for cytocritical care medicine.  And you�ll notice that they basically, we recommend against the routine use of neuromuscular  blocker infusion in adults with ARDS before optimizing mechanical ventilation and assessing ARDS severity.  And then at number two, they say to suggest that for moderate or severe ARDS, if they tolerate ventilation using a lighter sedation strategy, that again, they suggest against  using neuromuscular blockade. But what I want to skip down to is the number three, which is in adults with moderate or  severe ARDS who clinicians determine require ongoing deep sedation. And I actually should have bolded the words �deep sedation.� I bolded �moderate  or severe ARDS.� But really what I want you to focus on is that for ongoing deep sedation  and neuromuscular blockade to facilitate lung protective ventilation, we suggest, and again, it was a �suggest� in their guideline, using a neuromuscular blocker agent infusion  for up to 48 hours over intermittent boluses of a neuromuscular blocking agent. And so again, they did recommend using a continuous infusion over intermittent doses.  Now they sort of left it open a little by saying for up to 48 hours. And so whenever you�ll have a statement like that, it leaves it open to, you know,  the clinician�s judgment as to starting or stopping it. And I would point out that, you know, in the study with the best evidence for giving continuous  infusion, they gave it up to 48 hours. And so this raises an important question, well, what about 40 hours? What about 36 hours? What about 24 hours?  Next thing you know, what about an hour? And so I think you can see the problem when you�re using like this continuous flat-dose strategy and then allowing the time to vary.  Well, there�s another study that I think, one, it�s consistent with the guideline that was just mentioned.  And I think it might give us some insight as to what�s happening in this difference between Acurisis and ROSE trials.  And this was a retrospective cohort multicenter, though, and it attempted to count for some of the difference between these two large trials.  And basically what they found is that the neuromuscular blocking agent, and I put this in quotes, that it strongly depends on the proportion of deeper sedation during mechanical  ventilation. And basically neuromuscular blocking agent infusions add value in patients who need this deeper sedation.  And the patients requiring the deeper sedation in this study were the ones that actually had the beneficial effect.  And so this ends it up basically stating that maybe the difference really was due to sedation  strategies and the best argument for using continuous infusions are in patients who really do require deep sedation.  Again, these are the patients that should get the continuous flat-dose, high-dose cis-atricurium for 48 hours.  I will point out there was one concern that deeper sedation was an average of two times longer than the duration of neuromuscular blocking agent infusions that were typically  48 hours. In other words, the investigators, the authors, were arguing against this continuation of  deeper sedation even beyond the duration of the neuromuscular blocking agent infusion. So that's something that you look at pretty much no matter what.  So conclusions, there's basically conflicting results between a curiosis and ROSE, and it raises questions concerning the mortality benefit.  But all of the RCTs suggesting outcome benefits or trends towards benefits basically use 48-hour continuous flat-dose, high-dose infusions of cis-atricurium.  And so therefore, if neuromuscular blocking agent is used, you've got to recognize that there's really no substantial evidence of clinically important outcome benefits for  other dosing regimens such as intermittent bolus dosing, short-duration regimens, LOTUS infusions.  And so my point is, again, if you're going to go with this agent, you really need to go with the best evidence because there's little to no evidence of any benefit with  these other types of dosing strategies. And finally, going with the evidence, I'll just point out a little humor at the end here.  Although this story is actually true, that explorer Charles Waterden who demonstrated the effects of crude curare known as RORLE in three asses, and this actually again is  true as some of the early investigations of neuromuscular blockade. And in this case, the first ass, the shoulder was injected with curare and the animal died.  And the second ass, the tourniquet was tied around the foreleg. And then this was followed by this curare injection below level of tourniquet, and the  animal was alive until that tourniquet was removed, and then the animal died. And then the third ass, it died after the curare was injected, but they actually resuscitated  the animal with bellows. They named their animal RORLE, and basically that animal lived in peace for the rest of its life.  And it actually, when it did die, it was followed by an obituary in the local newspaper. So at least a happy ending for the third ass.  And so my conclusion as I look at this is to go with the best evidence, and thank you very much, and I hope you enjoy the rest of the meeting.

Video Summary

In this video, Brian Erstad discusses dosing strategies for paralytics in patients with acute respiratory distress syndrome (ARDS). He argues for the use of a continuous flat dose strategy based on the best available evidence. He mentions the ACURISIS trial, which found a reduction in mortality with the use of cisatracurium in a continuous infusion. He also discusses other trials that supported the use of cisatracurium in ARDS patients. However, he acknowledges that the ROSE-PETAL trial did not show a difference in mortality between cisatracurium and usual care groups. He highlights the importance of considering the context and clinical circumstances when deciding on dosing strategies. Erstad concludes that continuous flat dose strategies have the best evidence for improving outcomes in ARDS patients, and other dosing regimens have little to no evidence of benefit.

Asset Subtitle

Pharmacology, Pulmonary, 2022

Asset Caption

The use of neuromuscular blocking agents (NMBAs) has been established as part of the treatment strategy for patients with acute respiratory distress syndrome (ARDS). However, the optimal approach to dosing NMBAs for patients is still controversial. The 2016 Society of Critical Care Medicine guidelines on the use of NMBAs did not discuss whether to utilize a continuous infusion (titrated or flat dose) or intermittent doses. The two major trials to date, ACURASYS and ROSE-PETAL, both used a continuous infusion (flat dose) approach. However, with the numerous adverse effects associated with NMBAs, an intermittent strategy could be considered to reduce the total dose and lessen these adverse effects. Furthermore, the ROSE trial did not show benefit with a continuous infusion (flat dose) approach. This session will comprise two pro/con sessions that will discuss the therapeutic yield of neuromuscular blockade, dosing approaches to NMBAs in ARDS, and the monitoring and potential long-term sequelae of NMBAs.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Pulmonary

Knowledge Level Advanced

Membership Level Select

Tag Pharmacology

Tag Acute Respiratory Distress Syndrome ARDS

Year 2022

Keywords

dosing strategies

acute respiratory distress syndrome

continuous flat dose strategy

cisatracurium

mortality reduction

improving outcomes

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