SCCM Resource Library-Pro/Con: Block It or Drop It? Debating Neuromuscular Blockade for Acute Respiratory Distress Syndrome

Video Transcription

asking me to speak at the Society of Critical Care Medicine meeting. I'm honored to present  at a session entitled Pro-Con, Block It or Drop It, Debating Neuromuscular Blockade for Acute  Respiratory Distress Syndrome. I will be giving the pro talk concerning paralysis and ARDS, and this is in response to Dr. Gallagher from Emory University who gave the con talk.  I do not have any disclosures related to this talk, and I don't have any affiliation with an  organization whose philosophy could potentially bias my presentation. My research is also funded  by the National Endowment of the Arts and the NIH. I was fortunate to be one of the co-chairs  of the protocol committee with Dr. Derek Angus for the ROSE, or the Early Neuromuscular Blockade  in the Acute Respiratory Syndrome trial that was published in the New England Journal of Medicine  in 2019. The conclusion of this study was that among patients with moderate to severe ARDS  who were treated with a strategy involving high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous  cis-atrocuram infusion and those who were treated with the usual care approach with lighter sedation targets. The two key words in this conclusion are early and continuous  cis-atrocuram. This was not a study of neuromuscular blockade compared to no neuromuscular  blockade. Neuromuscular blockade was allowed as part of the ROSE protocol. First, it was allowed  prior to enrollment. So, if patients received neuromuscular blockade before they met inclusion  criteria for the study, they could be enrolled into the study, and they could even be enrolled  after they met the inclusion criteria for ARDS if they had received neuromuscular blockade,  as long as it was no more than two intermittent boluses of neuromuscular blockade, excluding  that neuromuscular blockade could be given for other reasons as opposed to just management of ARDS,  such as if the patient was being intubated or for procedure, and they could even receive a  continuous infusion of neuromuscular blockade as long as it was not for more than three hours  and that the clinical team agreed that it could be stopped. And as part of the protocol after  patients were enrolled into the study, patients in the control group could receive neuromuscular blockade as we wanted to respect clinician autonomy and protect patient safety while  preserving separation between the two groups with the amount of neuromuscular blockade that they received. So, if patients had refractory hypoxemia, we encouraged non-neuromuscular  blockade interventions, such as proning, deep sedation, and the consideration of a trial of  diuresis. And prior to the ARDS study published in JAMA, we allowed recruitment maneuvers, but  after the study, we discouraged them. If patients had a end-inspiratory plateau pressure of greater  than 32 centimeters of water for at least 10 minutes, we recommended that the bedside clinician tried potentially to increase in doses of sedation, decreasing the tidal volume,  and decreasing the PEEP. And if there was still a high plateau pressure, the treating physician  could give neuromuscular blocking agent in an open-label fashion, and we recommended 20 milligrams  of cis-acetracurin. If the neuromuscular blockade did not decrease the end-inspiratory plateau pressure by 2 centimeters of water, a second injection or infusion of 20 milligrams of  cis-acetracurin would be allowed. After that, we recommended that no more neuromuscular blockade  be given to the patients, if possible. You can see here in this table from the ROSE study  that patients in the control group did indeed receive neuromuscular blockade. Of importance,  the intervention group received 47.8 hours of neuromuscular blockade on average and 1,807  milligrams of cis-acetracurin. There were 14.8 percent of the patients in the intervention group  who had their neuromuscular blockade infusion stopped, and this was usually due to clinical  improvement. They didn't need it anymore. In the control group, in the first 48 hours, 17 percent  received cis-acetracurin at an average dose of 38 milligrams or two infusions. But you can see in  this table or in this figure here, in the dark gray, that patients did continue to receive  neuromuscular blockade at 48 to 96 hours and after 96 hours. And if you look at the entire duration  of the trial, up to 36 percent of patients in the control group did receive some degree of  neuromuscular blockade in an intermittent manner. So, I think we can conclude that the ROSE trial  was not a trial of neuromuscular blockade versus no neuromuscular blockade. It was a trial of  continuous neuromuscular blockade compared to intermittent neuromuscular blockade, and therefore,  I think it is reasonable to give patients intermittent neuromuscular blockade for the indications that were included into the study protocol. Another reason to potentially give  neuromuscular blockade to ARDS patients is when there's a significant amount of ventilator  dyssynchrony. And this has been brought forward and become seemingly more important during the  COVID-19 pandemic. Dyssynchrony is defined as an inappropriate timing and delivery of a breath by  the ventilator in response to a patient effort. And it's likely that ventilator dyssynchrony  propagates ventilator-induced lung injury through a variety of mechanisms, including large tidal volume trauma, high pressures barotrauma, and even atelectrauma.  In a study performed by Peter Satiel, who's one of the faculty here at the University of Colorado,  and the majority of the work I'm going to present from this time forward was work that Peter did,  he enrolled 62 patients who had hypoxic respiratory failure and at-risk diagnoses for ARDS  who were enrolled within 12 hours of intubation. These patients were pretty sick with an initial  P to F ratio of 139 and a mortality rate of close to 40 percent. Peter continuously recorded the  waveform from the patients over a period of time and over the course of the study collected over 4 million breaths on these 62 patients. On average, a median of 37 hours of data was  collected on each patient and 40,000 breaths. What Peter showed is, first of all, on average,  double-trigger breaths give you tidal volumes of close to 12 cc's per kilogram. And you can see  that of all the different types of dyssynchrony, double-trigger breaths accounted for about 4.1  percent of all breaths. The percentage of dyssynchronous breaths that were greater than 8 cc's per kilogram, the double-trigger breaths accounted for 54 percent.  You can see in this slide that neuromuscular blockade essentially eliminates most forms of  ventilator dyssynchrony. It's not perfect. This is likely due to the fact that when someone is  receiving neuromuscular blockade, it does not always mean that the patient is effectively neuromuscularly blocked. In the second study that Peter published in Critical Care in 2018,  this was the secondary analysis of the low tidal volume ventilation ARDS NET or ARMA study. What  Peter examined in this study is he wanted to see what was the effect of receiving neuromuscular  blockade during the first three days of that study on a variety of outcome variables. One was  surfactant protein D, which is a marker of epithelial injury. The second is von Willebrand  factor, a marker of endothelial injury, and interleukin A, a marker of systemic inflammation.  In this study, there are four groups that were stratified based on their treatment arm and their  initial P to F ratio. The initial P to F ratio of less than 120 was selected because this was the  cutoff in the papazian accuracy trial. Below a P to F of 120 is where the most benefit from  neuromuscular blockade was determined or seen. You can see in red here that patients who had  a P to F ratio of less than 120 with low tidal volume ventilation, that the exposure to neuromuscular blockade was associated with a decrement significantly in changes in markers of  epithelial cell injury, endothelial injury, and systemic inflammation, raising the possibility  that in certain patients neuromuscular blockade may be beneficial to decrease ventilator-induced  lung injury and systemic inflammation. The final study that Peter performed was published in the  Blue Journal again in 2018. He used the PREMIER database to try to see is there a difference  between different forms or different types of neuromuscular blockade. He studied patients who  were admitted to the ICU with a diagnosis of ARDS or an at-risk diagnosis for ARDS who received  mechanical ventilation and continuous infusion of neuromuscular blockade for at least two days  within the first two days of hospital admission. He then looked at the difference between the effects of receiving cis-atricurin versus vecuronium in a propensity-matched analysis.  What Peter determined is that if patients received cis-atricurin compared to vecuronium  that there was a difference in their length of ventilator days, their length of time in the ICU,  and their odds of discharge to home. Therefore, there might be some properties of cis-atricurin  compared to vecuronium that are beneficial if patients require neuromuscular blockade.  In conclusion, the ROSE study was a trial of early 48-hour continuous infusion neuromuscular  blockade. I think we can conclude from the study that intermittent neuromuscular blockade  was allowed in the control group and therefore may be effective or reasonable to try in a trial of  intermittent neuromuscular blockade while stabilizing patients, and that ventilator dyssynchrony is a potential reason to use neuromuscular blockade, and future studies  are necessary to adequately measure and determine the potential harm of dyssynchrony  in this patient population. Thank you again for the invitation to present, and I look forward to seeing all of you at future Society of Critical Care Medicine conferences in person.  Hello. Thank you for listening to my talk today. I am Julie Gallagher. I'm a critical care clinical pharmacy specialist in the acute respiratory ICU at Emory University Hospital,  and today I will be making a case against the routine use of neuromuscular blockade for acute respiratory distress syndrome, or ARDS. I have no disclosures to make.  ARDS is an acute inflammatory process leading to diffuse alveolar damage and impaired oxygenation.  Given the high mortality rates associated with ARDS, many therapies, both pharmacologic and  non-pharmacologic, have been investigated to improve outcomes. Neuromuscular blocking agents are one of the only pharmacologic therapies to have shown improvement in outcomes.  So, if we look at the positive side of people here, we see that early studies have shown that  neuromuscular blocking agents improve ventilator synchrony, decrease inflammatory response,  decrease oxygen consumption, improve oxygenation, and improve chest wall compliance, all through  the prevention of respiratory muscle contraction. However, the use of paralytics are not without risks. We know that they are associated with ICU-acquired weakness and polymyopathy,  specifically when used at high doses for long periods of time. The use of paralytics leads to  exposure to high doses of opioids and sedatives to ensure that patients have appropriate pain  and sedation control while they're paralyzed. Due to the nature of the patient not being able to  move, it is associated with an increased risk of VTE. And then, of course, there's always the  dreaded scare of the risk of patient awareness while they're paralyzed, which can lead to trauma  and PTSD. Given the known benefits and risks of using neuromuscular blockers for ARDS, there should  also be consideration for which paralytic to use, as there are a number of agents available that have  varying pharmacokinetic and pharmacodynamic characteristics. Fortunately, there is an agent  that has many ideal characteristics that make it suitable for use in this setting, and that would  be Cicatricurium, which is a non-depolarizing neuromuscular blocking agent. Some of the characteristics about it that make it an ideal agent include that it has organ-independent  metabolism via Hoffman elimination, so there is not a risk for accumulation in liver dysfunction  or renal dysfunction, which is common in critically ill patients. It has very minimal adverse effect  profiles, specifically adverse effects that are unique to Cicatricurium that are not shared with  other neuromuscular blocking agents. And then it's also short-acting, so it has a very fast on, but  it also has a very fast off, so it has a fast time to reverse all of its effects. Due to these ideal  characteristics, Cicatricurium is the most widely studied neuromuscular blocking agent in ARDS.  So this leads us to our first landmark trial, the ACQUIRISIS trial, which I know many are familiar  with, but there are some important highlights that I want to point out about this trial. So the ACQUIRISIS was our first larger, multi-center, randomized controlled trial that  was double-blinded. It included 340 patients early on in their ARDS, so average time to  enrollment was within 16 hours. And these patients had moderate to severe ARDS with a mean P to F  ratio of approximately 110. And investigators did use lung protective ventilation strategies with  an average mean tidal volume of 6 mLs per kg. The clinical intervention for this study was a  high-dose Cicatricurium infusion for 48 hours compared to placebo, which was deep sedation.  The results from this trial were largely positive, so the primary outcome of 90-day mortality  was not statistically significant, but did show a trend towards improvement with an absolute  reduction of almost 10%. In addition to that, there was statistical significance in some of  the secondary outcomes, specifically a higher number of ventilator-free days in days outside  the ICU in patients who received Cicatricurium. And there also didn't appear to be a significant  impact of harm, with no difference in the risk of ICU-acquired weakness, which was evaluated using the MRC score, which was measured at day 28 or at time of discharge.  While the findings from Acurasis were overall positive, in the decades since this study, there's been a continued and growing body of evidence that supports the use of  light sedation over deep sedation in critically ill patients. And the practice of early paralysis  may not have been as readily adopted as compared to other interventions that we know have a  mortality benefit in ARDS, such as lung protective ventilation strategy, prone positioning, and conservative fluid management. So not all providers were adopters of this practice.  So this doubt and hesitancy, coupled with the question of what is the role of light sedation  in this population, left room for our other landmark trial, which is the ROSE trial. Again, another study that most are likely familiar with, but this was, again, a multi-center  randomized controlled trial that this time was not blinded. It was larger with about 1,000 patients. Again, early ARDS with average time to enrollment of about seven hours,  moderate to severe patients, so a mean P to F ratio of about 100, and again, a lung protective  ventilation strategy with target tidal volumes of 6 mLs per kg. Clinical intervention was similar  with the high doses that were carried for 48 hours. However, this time the control arm were  patients who had a target of light sedation. So that was a RASF negative 1 to 0, a SAS of 3 to 4, SAS of 3 to 4, or a RAMSI of 2 to 3,  with about 30 to 40 percent of patients meeting this goal within the first 48 hours.  So, converse to our findings in the ACQUIRESIS trial, the ROSE trial failed to find any clinically significant differences in most of the outcomes. So there was no difference  in the primary outcome of 90-day mortality, which is about 42 percent for both arms. Also,  no difference in secondary outcomes, such as time on the ventilator or time outside the ICU.  There was no difference in the incidence of barotrauma or pneumothorax, and the investigators  did find an increased risk of serious cardiovascular events associated with cystic atricuria.  There are some important limitations to the ROSE trial that need to be discussed, as well as key  differences between the landmark trials. So we'll start with limitations to the ROSE trial.  So, a pretty high number of patients were excluded from enrollment because they were already receiving  continuous paralysis. So about 655 patients were included, which is not an insignificant number of patients, and might be excluding a patient population that is at risk for  paralysis, but a population that does benefit from paralysis. In addition to this, open-label  cystic atricuria use was allowed in both groups, with almost 20 percent of patients in the control  arm receiving at least one dose within the first 40 hours. So, again, leaving some open room for  interpretation of where paralytics played a role in AODS, and if there's various dosing strategies  Next, we'll talk about the key differences between the landmark trials, with the really  big difference being the level of sedation in the control arm. Again, the ROSE trial had patients,  the control arm targeted light sedation versus deep sedation. So is there a role for paralytics  when we're looking at patients with deep sedation? In addition to that, there were some key differences  in the management strategies between the two trials. So there was a low utilization of prone  positioning in the ROSE trial, which is a strategy that we know is associated with mortality benefit,  and then the ROSE trial utilized a higher peak strategy compared to Acurasis, which had a lower  peak strategy, with a higher peak strategy, maybe having some mortality benefit that could  have impacted the differences we see in the two trials. So what is the bottom line key takeaway  in my interpretation of these two very similar, yet very different studies? So I think a strategy  of continuous neuromuscular blocking is not appropriate for all comers of patients with  moderate to severe ARDS. Now there may be some consideration for select patients, such as those  who are requiring deep sedation, and there may be some consideration for select dosing strategies,  such as intermittent over a continuous infusion strategy. I also think a really key takeaway  that we find from the ROSE trial is that a target of lighter sedation is safe in this very sick patient population, and is an appropriate strategy for this group of patients.  Thank you so much for your time and attention.  Hi, my name is Heather Torbek, I'm a Medical ICU Clinical Pharmacy Specialist and the Critical Care PGY-2 Program Director at the Cleveland Clinic in Cleveland, Ohio.  My presentation is entitled Keep It Steady or Time for a Change, the Benefits of Intermittent or Train-of-4 Monitored Strategies.  As was previously discussed, there is currently limited data regarding the use of neuromuscular blockers in critically ill patients with ARDS.  Data to date has been mixed in terms of pros and cons associated with the use of neuromuscular  blockers in critically ill patients, largely due to the variations in study methodology and included patient populations.  Associated benefits have included improved oxygenation, decreased inflammation, increased ventilator free days, and even mortality depending on the study.  The use of neuromuscular blockers, however, is not without risk. Neuromuscular blockade has been associated with post-paralytic quadriparesis, post-traumatic  stress disorder from inadequate sedation while paralyzed, myopathy, skin breakdown, venous thromboembolism, corneal abrasions, prolonged recovery, and increased costs both from the  increased drug expenditure and increased costs for the healthcare system due to prolonged recovery.  One of the more concerning consequences of neuromuscular blockade use is ICU-acquired weakness, which could significantly impact the pace of recovery and result in significant  morbidity and mortality. The incidence of ICU-acquired weakness varies as the tools and scales used to diagnose it are inconsistently applied across studies.  There are a number of risk factors for ICU-acquired weakness, which have been identified, including  severity of illness, particularly multi-organ failure, and the need for mechanical ventilation  and or vasopressor support, sepsis, hyperglycemia, and neuromuscular blockade and steroid exposure.  In a 2016 meta-analysis, neuromuscular blockers were found to have a modest association with  critical illness-associated neuromuscular dysfunction, although these findings are limited by studies with high risk of bias and inclusion of patients with severe sepsis and septic  shock.  It's unclear what exposure to neuromuscular blockade therapy is necessary to result in  ICU-acquired weakness, and the cause is likely multifactorial given the additional risk factors patients on neuromuscular blocker therapy often have.  Given the potential risks associated with neuromuscular blocker use, it's prudent to limit neuromuscular blocker exposure.  One potential way to limit neuromuscular blocker exposure is with the use of train-of-four  monitoring, which was first used in operating rooms to assess for residual paralysis following surgical procedures.  For neuromuscular blockers to be titrated to train-of-four, a peripheral nerve stimulator must be placed on the patient.  The nerve stimulator is preferentially placed on the ulnar nerve, but can also be placed on the facial or post-tibial nerves.  The peripheral nerve stimulator is then started at 10 milliamps and increased in 10 milliamp increments until a patient has 4 out of 4 twitch response.  Typically baseline amplitude is 40 to 60 milliamps. The baseline amplitude should be used when patients are started on neuromuscular blockade  to assess response to neuromuscular blockade therapy. The goal train-of-four on neuromuscular blockade therapy is typically 1 to 2 twitches, which  corresponds to 85 to 90% of neuromuscular receptor blocking. The train-of-four is typically monitored every 4 hours while patients are on neuromuscular blockade therapy.  Surveys in recent years have sought to describe how clinicians are using neuromuscular blockers  in practice, especially with the ACQUIRISIS and ROSE trials using a fixed dosing strategy.  In a 2016 survey of adult intensivists practicing in the United States, 94% of respondents reported  prescribing either intermittent or continuous infusion neuromuscular blockers for patients  with ARDS, and 62.1% considered neuromuscular blockers to be their preferred rescue therapy.  Of intensivists prescribing neuromuscular blockers for ARDS, 62.5% reported using train-of-four  to monitor neuromuscular blocker therapy, suggesting that this is an established management strategy.  In light of the ROSE trial results, intensivists were resurveyed in 2020 to evaluate neuromuscular blocker prescribing practices.  96.6% of survey respondents said they used neuromuscular blockers for the management of ARDS, with 74.9% of intensivists using neuromuscular blockers for 25-48 hours.  In this survey, again, the most common method used for neuromuscular blocker dosing was train-of-four titration, with 68% of intensivists using neuromuscular blockers in this way,  despite the study methodology in clinical trials. If the two largest randomized controlled trials evaluating the use of neuromuscular blockers  for ARDS studied fixed-dose neuromuscular blocker dosing, why are over 60% of intensivists titrating neuromuscular blockers to train-of-four?  The 2016 SCCM Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient suggests using train-of-four monitoring in addition to clinical  assessment to monitor depth of neuromuscular blockade.  If the guidelines recommend train-of-four in conjunction with clinical assessment, how did we even get to fixed-rate continuous infusion dosing of neuromuscular blockers?  In 2004, Gainier and colleagues demonstrated a sustained improvement in oxygenation over 120 hours with the use of continuous infusion sesatucurium managed by a study nurse to  maintain blinding. Sesatucurium was bolused at 50 mg and then an infusion was initiated  at 5 mpq per minute and increased by 20% when the train-of-four was greater than or equal to 1.  In 2006, a similar management approach resulted in decreased inflammatory markers associated with neuromuscular blocker use.  Although train-of-four was used in these earlier studies, the train-of-four goal is much lower than our typical clinical approach and likely resulted in over-paralysis.  Based on the dosing strategies used in these studies, the ACQUIRISIS trial in 2010 used a  fixed dose of 37.5 mg per hour and resulted in a decreased 90-day mortality when adjusted for the baseline P-to-F ratio, plateau pressure, and SAPS-II score.  Since the ACQUIRISIS trial, there has not been a large randomized control trial which has  challenged this dosing strategy, as the ROSE trial also used a fixed rate of 37.5 mg per hour.  Ultimately, it's important to recognize that flat-dose, continuous infusion neuromuscular blocker was not developed out of efficacy or safety for patients. It was developed in a  research environment to blind investigators and bedside clinicians from neuromuscular blocker assignment or placebo. I think it's largely why these doses and regimens have  not been largely adopted by bedside clinicians in clinical practice.  With the large randomized control trials evaluating neuromuscular blockers in ARDS using a large fixed dosing rate, is there such a thing as over-paralysis,  and would alternative dosing strategies help reduce neuromuscular blocker exposure? This was an interesting study in that it sought to evaluate the agreement between subjective and  objective assessments of degree of paralysis. Essentially, how are clinicians on their own assessing depth of paralysis? The guidelines recommend using TRAINA-4 in conjunction with  clinical assessment, but how congruent are these assessments and what are the consequences of  over-paralysis? This was a prospective study of 119 patients who were diagnosed with over-paralysis  of 119 patients who required neuromuscular blocker therapy for greater than 24 hours, with 94 patients having ARDS. The investigators defined three levels of paralysis.  Over-paralysis was defined as a TRAINA-4 of zero, well-paralyzed was a TRAINA-4 of one to two,  and under-paralysis was a TRAINA-4 of three to four. Both ulnar and facial TRAINA-4 readings were obtained. These assessments were then compared to physician assessment  of degree of paralysis with physicians blinded to TRAINA-4 results.  The investigators found that the number of observed agreements between clinical assessments and facial TRAINA-4 measurements was 19.08% and 17.37% with ulnar TRAINA-4 measurements.  This is compared to ulnar and facial TRAINA-4 measurements, which were in agreement 62.75% of the time. Another interesting finding from this study was related to safety and  ICU-acquired weakness. The investigators found that the proportion of facial and ulnar TRAINA-4  equal to zero during the neuromuscular blocker treatment was significantly higher in patients  with ICU-acquired weakness compared to those patients without. There was no difference in  overall dose or duration of neuromuscular blocker therapy between patients who experienced ICU-  acquired weakness and those who didn't. This study highlights the inconsistency between TRAINA-4  and clinical assessment and supports the need for TRAINA-4 monitoring, especially from a safety  standpoint. Again, concerned with over-paralysis, associated adverse effects, and increased drug costs, a single-center study evaluated the implementation of a nursing-driven  sesaticurium titration protocol using TRAINA-4. They reported their experience in 30 patients  with ARDS and a P-to-F ratio of less than 120. They found that the nursing-driven protocol  resulted in significantly less neuromuscular blocker exposure compared to the dosing strategy used in the ACQUIRISIS trial. Patients were started on an average of 11.8 mg per hour  and uptitrated to an average final dose of 14 mg per hour. The investigators compared the average  cumulative dose of sesaticurium received by patients using this protocol compared to what they would have received if the ACQUIRISIS dosing strategy had been used instead.  The nursing-driven TRAINA-4 protocol resulted in a significantly lower neuromuscular blocker cumulative dose. Four patients experienced clinically diagnosed ventilator dyssynchrony  while on this protocol. Interestingly, the goal TRAINA-4 in the protocol was 0 out of 4, which 70% of patients achieved within the first hour of neuromuscular blocker initiation,  and 60% of patients did not require further dose adjustments. I think this demonstrates that  patients may still have been overparalyzed using this protocol despite the significantly lower  doses of sesaticurium compared to the ACQUIRISIS trial, and the optimal dose is likely unknown.  Risks associated with overparalysis like ICU-acquired weakness were not reported.  TRAINA-4 may be a strategy, however, to reduce neuromuscular blocker consumption and associated risks of these medications.  This was again studied in a single-center retrospective study of ARDS patients who received a sesaticurium infusion for greater than or equal to 12 hours.  Patients either received sesaticurium at a fixed rate of 37.5 mg per hour or titrated to a goal  TRAINA-4 of 1 to 2 twitches. There were 167 patients evaluated with a median baseline P-F  ratio of 97. The dosing strategies resulted in similar changes in the P-F ratio at 24 and 48  hours. The fixed dosing strategy was associated with a three-fold increase in drug exposure compared to the TRAINA-4 dosing approach. There was no difference in secondary endpoints,  including ventilator-free days, ICU length of stay, and hospital mortality. Although this is a retrospective study, it is larger than the nursing-driven protocol study  and again demonstrates that a TRAINA-4 dosing approach can reduce drug exposure without impacting clinical outcomes for patients.  Our fixed dose and TRAINA-4 dosing strategies are only dosing options.  Recently, a retrospective study of 189 patients with ARDS evaluated a ventilator-synchrony dosing protocol compared to patients who received fixed dose neuromuscular blockade  or TRAINA-4 titrated neuromuscular blockade. This study evaluated overall neuromuscular blocker consumption as well as change in P-F ratio and oxygenation index from baseline  up to 48 hours. Overall, drug consumption was significantly lower in the ventilator-synchrony  protocol group followed by TRAINA-4 dosing and patients receiving fixed dose neuromuscular blockade therapy having the highest drug consumption. There was no difference between  groups in terms of P-F ratio or oxygenation index. Although this was a single-center retrospective study with limitations related to the overall ARDS management strategies employed,  it highlights another management approach which may reduce neuromuscular blocker exposure  and subsequent harm while still providing the same benefits of more studied dosing approaches.  As discussed earlier in this presentation, the data evaluating the use of neuromuscular blockers in patients with ARDS has been inconsistent. If utilized, their use is  primarily to target ventilator-synchrony. The studies I've just presented demonstrate that we can achieve similar outcomes without overexposing patients to high-fixed-dose  neuromuscular blocker infusions. In both the ACQUIRISIS and ROSE trials, patients in the  control arms received more rescue neuromuscular blocker boluses compared to the sessatricurium  arms. In the ROSE trial in particular, 17% of patients in the placebo arm compared to 3% of  patients in the intervention arm received a rescue bolus with no difference in outcomes between  groups. An as-needed approach allows for assessment of response to neuromuscular blockers and temporarily eliminates most forms of ventilator-dysynchrony. This targeted approach  allows physicians to assess the impact of neuromuscular blockers on ventilator-dysynchrony  and make subsequent ventilator changes prior to additional neuromuscular blocker administration.  For the majority of patients, a bolus-dose approach is likely sufficient to facilitate  ventilator synchrony, but for patients requiring multiple bolus doses of neuromuscular blockers,  a continuous infusion should be initiated with consideration for titration to train a fore and clinical response to minimize neuromuscular blocker exposure.  Despite the available data, I think we are still lacking data in regards to the best dosing approach if neuromuscular blocker therapy is indicated in patients with ARDS.  A dosing strategy utilizing TRAINF4 for titration has been shown to decrease neuromuscular blocker  consumption. The data I've presented suggests that a TRAINF4 dosing strategy could on average  decrease the dose of neuromuscular blocker therapy needed in patients with ARDS to one-third of the  fixed dose rate currently used in the ACQUIRISIS and ROSE trials. With decreased neuromuscular  blocker consumption comes reduced drug costs. In the previous trial I presented, they reported  that the mean cost of cesatocurium per patient using a TRAINF4 dosing strategy was approximately  $1,500 per patient versus almost $4,000 per patient when using a fixed-dose approach.  This is of particular interest in light of the COVID-19 pandemic and the surge of patients with ARDS and corresponding drug shortages which have impacted some hospitals' access to  neuromuscular blocker therapy. Additionally, reduced neuromuscular blocker doses could result  in lower volumes of fluid administered. We know from the FACT trial that a conservative fluid management strategy improves lung function, decreases ventilator days, and reduces ICU  length of stay compared to a liberal approach. Patients with ARDS are often receiving numerous IV fluids including approximately 2 liters a day from neuromuscular blocker therapy  when using a fixed-rate dosing strategy. A TRAINF4 dosing strategy reduces the cumulative neuromuscular blocker dose which could also impact morbidity and mortality in regards to  consequences related to fluid overload. Finally, in a one-size-fits-all fixed-dose approach, we do not account for differences in pharmacokinetics and pharmacodynamics among  patients. Although cesatocurium and atrocurium are the most commonly administered continuous neuromuscular blocker infusions and could minimally be impacted by end-organ damage,  there may still be a risk of metabolite accumulation and risk of neurotoxicity.  The impact of weight on neuromuscular blocker dosing in patients with ARDS has not been assessed,  but data extrapolated from single doses or short-term infusions in the perioperative setting suggest that obese patients are at risk for accumulation and prolonged recovery times  when actual body weight was used to dose non-depolarizing neuromuscular blockers.  The current SECM guidelines recommend using an ideal or adjusted body weight to dose neuromuscular  blockers when the BMI is greater than or equal to 30 based on this data. Therefore, a fixed-dosing  approach to neuromuscular blockers in patients with ARDS increases the risk of overparalysis  in underweight patients and overparalysis in obese patients, thereby impacting treatment success  and risk of adverse effects. I don't believe that there is a one-size-fits-all dosing approach to  neuromuscular blocker therapy. Neuromuscular blockers are not benign. We must not get  complacent when adding this therapy to a patient's management strategy. Patients must be frequently  reassessed to ensure that the therapy is meeting our intended goals. A multifaceted approach to  neuromuscular blocker management such as bolus dosing, train-of-four, and clinical assessment should be employed to reduce neuromuscular blocker exposure and reduce the likelihood  of adverse effects, including ICU-acquired weakness, thereby impacting recovery and increasing morbidity and mortality. 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.  In 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 and 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  at 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. And 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 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 multi-center, randomized controlled trial. And they were  looking at TRNF4 and using cis-atricurium, and basically using cis-atricurium either to maintain a TRNF4 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 TRNF4 of 0 to 4. And basically, if you  look at their conclusions, the blockade to achieve a TRNF4 of 2 of 4 provided similar respiratory benefits as TRNF4 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 TRNF4.  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 of years later, another multi-center 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 a cis-controlled 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 multi-center 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. They had 340, 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, assist control of tidal volumes of 6 to 8 mils 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 milligram bolus followed by a continuous flat dose infusion  of 37.5 milligrams 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, you know, zero to four, a train of four. And so again, it was  done on purpose. And the idea that you wouldn't have to do any train of four monitoring and  realize train of four monitoring is controversial in and of itself. There's a lot of ways to misinterpret the findings, placement issues. Again, there's not high level evidence for  train of four. And in the guidelines, we basically recommend it as one part of a number  of clinical strategies for evaluating neuroblascular blockade. But in this study, they just frankly  wanted to get around it. And so train of four 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-atricuria. You can see the 0.68 and that 95% confident interval was statistically significant.  And this had the adjustments you see there on the slide. The crude mortality, again,  there was a trend here. You know, 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 listeners 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 neuromuscular blocking agent guidelines. Well, there was a lot of discussion of these various studies and especially the AcuraSys  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 were 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 Cis Atricurium versus Vecuronium. And in this case, Cis Atricurium 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 for using Cis Atricurium. And whether it's due to a unique beneficial  effect of Cis Atricurium, 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 Cis Atricurium 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 Cis Atricurium, 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. The trial was  stopped for utility. And when they ultimately looked at mortality, there was no difference between Cis Atricurium 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 Cis Atricurium 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. It 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 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 Cytic Critical 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 they, at number two, they say to suggest that for moderate or severe ARDS, if they tolerate ventilation using a lighter sedation strategy, 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 suggestion 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 Acurisys 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-atrocurin  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 Acurasis and Rose, and it raises questions concerning the mortality benefit. But all of the RCTs suggesting outcome benefits or trends towards  benefits basically used 48-hour continuous flat dose, high dose infusions of cis-atrocurin.  And so therefore, if neuromuscular blocking agent is used, you 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 Rorale 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 the animal Roralea 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

The video provides an overview of the use of neuromuscular blockade for acute respiratory distress syndrome (ARDS) and discusses different dosing strategies. The speaker presents evidence from various clinical trials, including the ACURISIS and ROSE trials. The ACURISIS trial showed a potential benefit with continuous infusion of cisatracurium for 48 hours, while the ROSE trial did not find a significant difference in mortality between continuous infusion and usual care with lighter sedation. The speaker argues for the use of continuous flat-dose strategies based on the best available evidence. They also highlight the importance of considering the clinical context and individual patient factors when deciding on the dosing strategy for neuromuscular blockade in ARDS. Overall, the speaker emphasizes the need for evidence-based decision-making and caution against relying on anecdotal information in determining the appropriate use of neuromuscular blockade in ARDS.

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. Learning Objectives: -Explore the controversies surrounding the therapeutic benefit of neuromuscular blockade for acute respiratory distress syndrome (ARDS) -Compare administration strategies for neuromuscular blockade including intermittent doses and continuous infusions -Compare and contrast efficacy and discrepancies in the literature on paralysis in patients with ARDS

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Pulmonary

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Pharmacology

Tag Acute Respiratory Distress Syndrome ARDS

Year 2022

Keywords

neuromuscular blockade

acute respiratory distress syndrome

ARDS

dosing strategies

ACURISIS trial

ROSE trial

continuous infusion

mortality

sedation

evidence-based decision-making

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