hosted and supported by the Society of Critical Care Medicine is part of the Journal Club Critical Care Medicine series. In this webcast we feature co-authors of two viewpoint articles from the April issue of Critical Care Medicine. Each will present their case as to a pro-con debate. My name is Thomas Zagmany and I'm here to introduce you to our presenters. But before I do that, please note the following. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion or other information that may be mentioned. Now, a little bit about our presenters. Ivan Koh is a Clinical Assistant Professor in the Departments of Emergency Medicine and Internal Medicine, Division of Pulmonary and Critical Care at the University of Michigan. He is board certified both in emergency medicine and critical care medicine. Dr. Koh completed his degree in medicine from the Chicago Medical School at Rosalind Franklin University of Medicine and Science and then went on to the University of Illinois, Chicago, where he completes his residency training in emergency medicine. He joined the faculty at the University of Michigan after completing his fellowship training in internal medicine critical care with the Division of Pulmonary and Critical Care at the University of Michigan. Dr. Koh's academic interest focuses on real-time critical care education at the bedside, airway management in the intensive care unit, role of bedside ultrasound in the ICU. His clinical interests include varying critical care illnesses from acute respiratory distress syndrome, ARDS, sepsis to pulmonary embolism. He is currently a co-investigator for the University of Michigan site of the NIH, Prevention and Early Treatment of Acute Lung Injury, PTAL network. He is also involved in multiple educational committee for the emergency medicine as well as for the Pulmonary Critical Care Fellowship training program. Alexander H. Flannery is an assistant professor at the University of Kentucky College of Pharmacy and Medical Intensive Care Unit, pharmacist at the University of Kentucky Healthcare. He is the residency program director for the PGY2 critical care residency at UK Healthcare. Dr. Flannery completed his pharmacy practice residency at the Medical University of South Carolina and PGY2 critical care residency at the University of Kentucky where he has practiced since 2013. He is an active member within SCCM's clinical pharmacy and pharmacology section and the society at large. Thank you both for joining us. Ivan, we will start with you and then Alex. Thank you, Tamaz. My name is Ivan Koh and I will be presenting the viewpoint on rescue neuromuscular blockade in ARDS should be flat dose. I do not have any disclosures to report. So before we talk about why rescue neuromuscular blockade should be flat dose for ARDS, a couple of things that is important to keep in mind is what are some of the benefits of neuromuscular blockade in acute respiratory distress syndrome. Some of the things that are here for review is essentially to help facilitate prone ventilation, helps limit ventilator associated lung injury, limits ventilator dyssynchrony, work of breathing, and as a result accumulation of alveolar water. And there's some literature that helps decrease lung inflammation. And so neuromuscular blockades comes in two different classes, the aminosteroids as well as the benzyl isoquinoliniums. Most recently, at least in the last 5-10 years or so, the benzyl isoquinoliniums are the more prevalent neuromuscular blockade used for ARDS. And these are the cisatricurium that we have been using clinically. Prior to this, the aminosteroids such as racuronium and vacuronium were the more common ones. They both mechanistically act the same way, they're non-depolarizing. The big difference between the two groups of neuromuscular blockades are its drug clearance. The aminosteroids are hepatically and or venally cleared. However, the benzyl isoquinoliniums are cleared through Hoffman elimination. There are some reversal agents with the aminosteroids, which are the sugamidex. The onset of actions as well as duration of actions are pretty much the same. With that being said, let's look at the two most recent trials for neuromuscular blockades in ARDS. These are the ACRIBISIS as well as the ROSE trial, which came out a year or two ago. Both of the trials used cisatricurium as the neuromuscular blockade of choice. The dose is outlined here, which is a bolus of 15 mg followed by a 37.5 mg per hour infusion, which are fixed dose. The duration was done at 48 hours, and they both used the Ramsey sedation scale for monitoring. There was no nerve stimulator or chain of four used between these two trials. And so outside of the randomized control trial environment, why flat dose over variable dosing? As well as less prone to administration errors. However, if we were to take the argument that dose adjustment should be used over flat dose for neuromuscular blockade in ARDS, there are a few assumptions that I think that we need to make clinically. Number one, flat dose results in more drugs being administered, leading to prolonged ventilation and this notion of increased ICU acquired weakness. Neuromuscular blockade is associated with ICU acquired weakness. And in order for us to actively adjust doses for variable dosing, we need to have a valid tool to measure assessment of paralysis, which we'll go through some of the slides here. But there is no good tools for measuring paralysis clinically. So ICU acquired weakness has been studied over and over again. It is a complex pathophysiological process. It's multifactorial as it pertains to critical care. There are issues as it pertains to lack of nutrition, limited mobility, inflammation, drugs, particularly corticosteroid. There has been a lot of studies that has attempted to look at neuromuscular blockade and ICU acquired weakness. The good correlation that has been found previously was the association of neuromuscular blockade with aminosteroid and corticosteroid administration in mechanically ventilated asthma patient. Outside of that, it is very hard to find studies correlating between neuromuscular blockade and ICU acquired weakness. And why? Why is it that the aminosteroids are the ones that has been linked with ICU acquired weakness, but not the cis-atrocurams? The hypothesis surrounding that is patients with critical illness also have subsequent injury to the kidneys as well as to their liver, which results in prolonged drug clearance, which results in prolonged neuromuscular blockade. So neither ACQUIRISIS nor the ROSE trial found correlation between neuromuscular blockade and ICU acquired weakness, and both studies used fixed dose. There are a lot of new critical care practices that we have been implementing this past 10-15 years that has mitigated some of the known factors associated with ICU acquired weakness. And these are not limited to improvement in mobility, light sedation, and early neuromuscular blockade cessation, the development of cis-atrocuram with Huffman elimination, early nutrition, and then more cognizant discontinuation of drugs in the ICU. The other arguments for fixed dose dosing is the notion that we do not have a way to measure the level of paralysis when you try to dose adjust neuromuscular blockade. Two common bedside tools that we've used for assessment of paralysis are the peripheral nerve stimulator as well as the Trana4. They're not reliable in the ICU when compared with clinical assessment, and these are because a lot of our patients have regional peripheral edema, there are variability with the location for monitoring, there's some issues with skin resistance and diaphoresis. These two tools were validated in the operating room, and trying to translate things from the operating room to the ICU has had its limitations, and the peripheral nerve stimulation and Trana4 are not the only tools that had issues translating from the OR to the ICU. So to summarize briefly, as it pertains to neuromuscular blockade and monitoring, neither ACRIOSYS nor the ROSE trial, which are the two prominent trials in neuromuscular blockade and ARDS, used any sort of monitoring, including Trana4 or peripheral nerve stimulator in their clinical trial, with the ability that both ACRIOSYS and ROSE have of achieving some sort of a clinical outcome. ACRIOSYS achieved positive clinical outcome with neuromuscular blockade without monitoring, while the ROSE trial achieved no difference in clinical outcome with the use of neuromuscular blockade without monitoring. Both studies found that clinical assessment performed just as well without having to lower neuromuscular blockade dose, as well as noted to have improvement in recovery time when compared to Trana4s. The Society of Critical Care Medicine recommend against the use of peripheral nerve stimulator and Trana4 during neuromuscular blockade administration. Some of the questions that got brought up as it pertains to the viewpoint today is, how is neuromuscular blockade administered at my institution? At my institution, we use cis-satricurium and the modality of medication administration has been to administer it flat dose, similar to the protocol that is used in ACRIOSYS as well as the ROSE trial. The second question pertains to the use of paralysis in COVID patients. And as you guys are all well aware, the past couple of months had an increase in COVID ARDS. As far as I know, my institution has not had any notable increase in neuromuscular blockade use in trying to treat patients with COVID ARDS. This ends the part of my talk. I am now going to be turning it over to Alex. All right. Thank you, Abhi. My name is Alex Flannery from the University of Kentucky. And I'll be discussing the counter viewpoint that rescue neuromuscular blockade and acute respiratory distress syndrome should not be flat dose. And before we begin, I'd like to acknowledge my collaborator on the viewpoint, Dr. Mark Moss from the University of Colorado, who assisted in writing the viewpoint for critical care medicine. And I have no disclosures or conflicts of interest to report. But as a spoiler alert, our argument for this particular viewpoint is primarily based upon the premise that we think flat dose is more than the patient needs for this particular scenario. And so if you're watching this as really a preface to the rest of the viewpoint, one of the things that I would challenge you with is to name one other therapeutic agent that we knowingly administer to patients in higher doses than needed. So before we get into talking about dosing of the continuous infusions, I think one of the key points that Dr. Moss and I wanted to make was that first and foremost, before you even get to the continuous infusion, it's a very reasonable approach to try bolus PRN as needed approaches. And this is even supported by data from the ROSE trial. If you look at the intervention and control groups who received other neuromuscular blockers during the first 48 hours, 17% of the control group, almost one out of every five patients in that group did receive other neuromuscular blockade. And these two groups had very similar outcomes in terms of clinical outcomes and respiratory outcomes related to ARDS. And so based on this, we think that it sort of augments the argument that before you even start with the continuous infusion, it's a very reasonable approach to try a one time or PRN bolus dosing that allows you to alleviate some of the ventilator to synchrony and assess the patient's response to neuromuscular blockade for further decision making. So if you've tried the PRN approach and the PRNs aren't necessarily working and you're going to move to a continuous infusion, that's where the debate comes in about the dosing strategy to use at this particular juncture. And so our second point was that in some of these pilot studies that really paved the way for how the flat dose of 37.5 milligrams per hour was designed and subsequently used in the larger FRENCH trial that showed a benefit of neuromuscular blockade and ARDS, the flat dose was actually designed to be more drug than needed. Here's these two studies and really key points of them. A non-blinded nurse started the infusion of sesatricurium at five micrograms per kilogram per minute, increased the infusion 20% when the train of four was one or greater. So this is a key point is that their goal was actually no train of four response at all. And if they got there, the infusion was maintained. Now, for those of you that use train of four at your institution, you'll notice that zero out of four typically is not your goal. That's a little bit more of an aggressive goal than what I think a lot of places that are using train of four are using. So that's one of the key points here to notice in terms of how these dosing strategies were used in some of the pilot studies. So key takeaways from these pilot studies, and these are direct quotes, an abolition of all twitches of the train of four, and quote, no provision was made for potential overdosage of the drug. And in particular with that second quote, if you really think about dose finding studies in terms of traditional drug development, no provision for potential overdosages is really inconsistent sort of with our normal process for how we go about developing dosages for different drugs to use. And so from these particular pilot studies, you can see there that patients received about 1300 plus or minus milligrams of cesetricurium during the 48 hour period. So based on the data from these pilot studies, the flat dosing of 37.5 milligrams per hour times 48 hours for a total course of 1800 milligrams was developed and used in not only the French trial, but also in the Rose trial as well. Our third point was not only was flat dose designed to be more than needed, but it actually is more drug than needed. And there's a few pieces of evidence that point to this. The first being an analysis of the Rose trial. If you look at the intervention group, the group that received the flat dose of 37.5 milligrams per hour, and look at the actual number of patients that required an additional bolus, it's only 3.3%, very small percent of the intervention group, really suggesting that the majority of patients have a sufficient, if not excessive amount of drug on board such that they don't actually require any more additional as needed bolus dosing. This concept that flat dosing is more drug than needed is also supported by additional data from patients that have used alternative dosing strategies and compared the amounts to the flat dosing strategy. So there was a French study in 2017 that compared a nurse driven train of four protocol targeting zero out of four with Cistatricurium versus the flat dosing of the larger French trial of 37.5 milligrams per hour. And in using the train of four, you can see the hourly doses were reduced by over half, 14 plus or minus four versus 37.5 milligrams per hour. And the cumulative amount of neuromuscular blockade received was also approximately one third of that from the flat dose trial. So 700 plus or minus about 2000 milligrams. In an abstract that was presented in 2019, this was a retrospective study comparing a nurse driven train of four protocol of Cistatricurium versus the flat dose of 37.5. And again, very similarly to the prior study, the amount of drug that was received cumulatively over a 48 hour period was about a third of the amount received with the train of four dosing as compared to the flat dose. And importantly, there were no differences in surrogate outcomes such as a PF ratio or even clinical outcomes such as mortality by using these alternative dosing approaches that allowed you to use less drug. Now, on the other side of this viewpoint, it is a very valid argument that yes, flat dosing might be too much, but so what? What harms are there clinically from a non-steroidal neuromuscular blocker that is rapidly broken down by plasma esterases? And from a clinical standpoint and a weakness standpoint, I think that's a very valid argument for discussion, but there are at least two points that I think are pretty undeniable with the use of flat dose Cistatricurium. And one of them is that this drug is relatively expensive. So for a 48 hour course of it, in many centers, it's gonna be one to $2,000. And so if you multiply that by the amount of patients with severe ARDS that you care for every year, you likely end up with potentially hundreds of thousands of dollars per year of expenditures in this drug that could potentially be allocated towards equipment or staff that are known to improve clinical outcomes. Remember, we're using this drug from the ROSE trial that didn't necessarily show clinical benefits to use. And so allocating these particular funds to other potentially more beneficial investments might be a wiser choice of funds to use for your intensive care unit. Secondly, depending on how it's compounded, Cistatricurium can involve relatively large volumes of diluent or carrier fluid. So flat dose over the 48 hour period, it may be more than two liters of just diluent or carrier fluid alone. And we're talking about a patient population that based on the FACT trial and other literature, we know that patients with ARDS do better when they're on the dry side. And so if we're continuing to give them more drug than is needed by using this flat dosing strategy, we're also giving them more volume probably than they need, which again, we know is associated with more detrimental outcomes. At this point, I think it's also helpful when assessing the equipoise around the question to ask what other centers around the country are doing in terms of how they're using neuromuscular blockade in patients with ARDS. And this was a survey of academic intensivists on their dosing strategies. And while two thirds approximately reported using TRAINF4, only less than 10% reported using the fixed dose. So across all of the centers that responded to this particular survey, only a minority of intensivists are using the flat dose combination of 37.5 milligrams per hour. And the majority are opting towards a more titrated approach. So if we're suggesting that a titrated approach is the superior method for administering neuromuscular blockade via continuous infusion, what do we use? How do we titrate it? Society of Critical Care Medicine clinical practice guidelines offer some input here. And they suggest that TRAINF4 monitoring may be useful to monitor the depth of blockade. Now, they're not saying that TRAINF4 is the end goal. It has the caveat that only if it's incorporated into a more global assessment, including a clinical assessment of the patient. Which brings us to the next segue of what is an acceptable clinical parameter that you would titrate a neuromuscular blockade infusion to in ARDS? And this is one of the areas, I think that has not made the jump very well from an academic and a theoretical discussion based on what has been published into actually implementing into clinical practice. And it's been difficult because I think defining some of these terms into a titratable protocol that meets regulatory requirements for an order set or an order has been a particular challenge. So there is not one of these that is particular superior to the other. These are concepts though that have been proposed as to what may be an acceptable clinical parameter for titration. And they include plateau pressures of less than 30 or 35, peak pressures of less than 40, driving pressures of less than 13 to 15. And there are even some centers that are actually implementing this into their protocol of using transpulmonary pressure via the esophageal pressure monitoring. So again, operationalizing some of these has really been the challenge, but there are clinical parameters that correlate with outcomes in ARDS that it would make very logical sense to titrate the neuromuscular blockade too. Now, the gold standard for this should really be ventilator to synchrony, which then goes, well, how do you define ventilator to synchrony? And this protocol from Strange and colleagues may give us sort of some insight into how this is operationalized. They tested a TRNF4 protocol versus a best clinical assessment using atricurium, which is a very similar drug to cis-atricurium. And the best clinical assessment consisted of really a subjective determination of whether ventilator synchrony was maintained and the dose that prevented clinical movement. And the dose was assessed every 12 hours by lowering the dose to a dose that allowed the patient movement and then maintaining slightly higher than that. And when they compared outcomes between the two groups, the best clinical assessment or the TRNF4 protocol group, the dosing used and the time to clinical recovery were very similar between groups. And then as a final point to our viewpoint that the dose should not be necessarily a flat dose, I think one of the things that sometimes happens in practice is it's very easy to say the study protocol was a flat dose for 48 hours. And so that's what we should implement. Whereas it may not necessarily be that the patient even needs the neuromuscular blockade for 48 hours. And so if you're using an approach that involves down titrations, if you will, that can be a nudge to help you come off of the neuromuscular blockade sooner. And if you come off of the neuromuscular blockade sooner, you can lighten sedation sooner, which is obviously associated with better outcomes as well. And there's some data from the ROSE trial that demonstrates this may be useful. Even in the intervention group, about 15% of the group met the criteria for an early stopping allowance, which was sustained ventilator weaning for 12 hours or more defined by an FIO2 of less than 40% and a PEEP of less than or equal to eight. So really our final argument for not using flat dose is that if you're continuing to titrate, it may sort of help nudge you even closer to stopping the drug sooner than you might if you were doing a flat dose for a 48 hour period per a study protocol. So as closing thoughts, I think part of our main arguments were that bolus dosing and even using less than 48 hours of these continuous infusions if you can are encouraged. So this isn't an approach necessarily that's like the Showtime rotisserie infomercial, right? The set it and forget it. What I think we're suggesting is to use the minimum amount of drug needed to get the job done for the particular clinical indication and really not any more than that. And I think that's very consistent with a lot of the themes that come from the Choosing Wisely campaign. And so it's in that sort of vein that we've argued that using flat dose is really more drug than needed. It was designed to be that way and it actually does deliver that much more, two to three times as much drug really as a patient needs. And whether that is associated with really clinical outcomes from a weakness standpoint is less clear. But what is clear is that that does add substantial volumes of fluid as well as costs to that particular patient encounter. And so for that reason, we've taken the view in this viewpoint that flat dosing should not be the way to dose neuromuscular blockade and severe ARDS. Okay, here are a few questions that I've received on this topic, which I'll do my best to answer. The first one is how do you dose neuromuscular blockers in your institution, flat dose or targeted dose? I'd say we're in a shifting pattern right now. I think prior to publication of the ROSE trial, we had definitely evolved to a flat dose MICU. And then with the sort of subsequent publication of ROSE and really what it meant for neuromuscular blockade in ARDS, I think we were successfully sort of making the argument that flat dose was probably excessive and really start to see a greater movement back to the train of forward titration protocol, while also bringing our physicians and our nurse practitioners really into the assessment of ventilator to synchrony in terms of what the exact dose could be for the neuromuscular blockade in that individual patient. The second question is, have you changed your practice at all in light of the COVID-19 pandemic, neuromuscular blockade use has increased significantly in many centers? And really, depending on the challenges of the drug shortages faced, I think this was another impetus to really start moving away from the flat dose, just because if the paralytics were going to be on short supply, making sure that we were being very conscientious with how we use them, which again, like we argued in the viewpoint, I think not using a flat dose is probably a more conscientious use of these particular agents. And so I think we started to really look at ways to de-emphasize the flat dose for continuous infusion paralytics. And then we also made sure that we were supporting this concept of using bolus dosing first, instead of continuous infusions. And that if cetracurian did go on shortage, that we had protocols in place for other paralytics like rocuronium and vecuronium infusions, even though we have historically preferred to use cetracurian infusions solo, making sure that we had protocols ready to roll out for other neuromuscular blockers should the need arise to. Third question is, are you aware of any ongoing studies in this arena? I'm not aware of any particular large randomized trials that are necessarily going on with neuromuscular blockade in ARDS. I know there were several sort of different opinions when you compare and contrast the ROSE trial with the larger French study, and why they may have showed different results necessarily. I know a few different places that are continuing to look at retrospectively and observational nature of the outcomes between a flat dose strategy and a titrated strategy, whatever that might be, but I'm not necessarily aware of any large clinical trials. That are looking into this particular area. And then the final question is, what would be your top three research questions for the future? And so as it relates to the topic of paralytics in ARDS, I think one of the questions that's gaining traction as additional data comes out about phenotyping ARDS patients whether that's based on a biomarker or whether that's based on clinical parameters is there a subgroup of patients that would potentially benefit from neuromuscular blockade in ARDS? I think in terms of what to actually titrate to, I think as additional data emerges with ventilator management and really what the ideal targets might be, whether that's driving pressure or something else, that may be a useful tool that potentially validates some of those measurements as better surrogate markers for what you would actually titrate your neuromuscular blockade to. And really defining ventilator to synchrony I think would be very helpful in terms of making a very objective joint commission friendly order set slash protocol that could be implemented at a lot of different centers. And then finally, I think if you were ever going to do this study again, it would be really interesting to look at a PRN only approach of neuromuscular blockade versus a continuous infusion approach of neuromuscular blockade. I think as we talked about already, I think there's a lot of benefits to the PRN only approach if nothing else from the fact that it really forces you to constantly reevaluate and you're no longer getting paralytic if you don't necessarily need to. And so whereas you would be continuously deeply sedating patients with a continuous infusion neuromuscular blockade approach, potentially the PRN approach would offer you an opportunity to reinforce lightning sedation sooner. So I think that would be an interesting question to look at as well. So with that, that marks the end of my presentation and I'll now hand it back over to Tomas who will close out the webcast. Thank you. Thank you, Alex. And thank you, Ivan, for your presentations. And thanks to all of those who have taken the time to listen to this webcast. To register for future Journal Club Critical Care Medicine webcasts, visit secm.org slash webcasts. This concludes our presentation.

rescue neuromuscular blockade

acute respiratory distress syndrome

flat dosing

neuromuscular blockers

dosing errors

ventilator synchronization

ICU-acquired weakness