SCCM Resource Library-Dosing Strategies for Paralytics in ARDS: Keep It Steady or Time for a Change? Benefits of Intermittent/TOF-Monitored Strategies

Video Transcription

Hi, my name is Heather Torbek, and 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 four out of four 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 one to two twitches,  which corresponds to 85 to 90% of neuromuscular receptor blocking. The train-of-four is typically monitored every four hours while patients are on neuromuscular blockade therapy.  Surveys in recent years have sought to describe how clinicians are using neuromuscular blocker  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 to 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. With the two largest randomized control 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 suggest 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, Sasatcherium, managed by a study nurse to maintain blinding.  Sasatcherium was bolused at 50 mg, and then an infusion was initiated at 5 mpqpm 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 ACQUIRESIS 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-F ratio, plateau pressure, and SAPS-2 score. Since the ACQUIRESIS 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 and 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 TRAINA4 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 acquired 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 TRAINA4 of zero, well-paralyzed was a TRAINA4 of one  to two, and under-paralysis was a TRAINA4 of three to four. Both ulnar and facial TRAINA4 readings were obtained.  These assessments were then compared to physician assessment of degree of paralysis with physicians blinded to TRAINA4 results.  The investigators found that the number of observed agreements between clinical assessments and facial TRAINA4 measurements was 19.08% and 17.37% with ulnar TRAINA4 measurements.  This is compared to ulnar and facial TRAINA4 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 TRAINA4 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 TRAINA4 and clinical assessment and supports the need for TRAINA4 monitoring, especially from a safety standpoint.  Again, concerned with overparalysis, associated adverse effects, and increased drug costs,  a single-center study evaluated the implementation of a nursing-driven Sasatche Curiam titration protocol using TRAINA4.  They reported their experience in 30 patients with ARDS and a P-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 Sasatche Curiam 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 TRAINA4 protocol resulted in a significantly lower neuromuscular blocker cumulative dose.  Four patients experienced clinically diagnosed ventilator dyssynchrony while on this protocol.  Interestingly, the goal TRAINA4 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 Sasatche Curiam compared to the ACQUIRISIS trial, and the optimal dose is likely unknown.  Risks associated with overparalysis like ICU-acquired weakness were not reported. TRAINA4 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 Sasatche Curiam infusion for greater than or equal to 12 hours. Patients either received Sasatche Curiam at a fixed rate of 37.5 mg per hour or titrated  to a goal TRAINA4 of 1 to 2 twitches. There were 167 patients evaluated with a median baseline P to F ratio of 97.  The dosing strategies resulted in similar changes in the P to F ratio at 24 and 48 hours.  The fixed dosing strategy was associated with a three-fold increase in drug exposure compared to the TRAINA4 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 TRAINA4 dosing approach can reduce drug exposure  without impacting clinical outcomes for patients. Our fixed-dose and TRAINA4 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 TRAINA4 titrated neuromuscular blockade.  This study evaluated overall neuromuscular blocker consumption as well as change in P to 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 TRAINA4 dosing and patients receiving fixed-dose neuromuscular blockade  therapy having the highest drug consumption. There was no difference between groups in terms of P to 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 CISATCHICURIUM 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 4 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 train of 4 for titration has been shown to decrease neuromuscular  blocker consumption.  The data I've presented suggests that a train of 4 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 sesatocurium per patient  using a train of 4 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 train of 4 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. Though sesatocuram and atracuram 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 SCCM 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. Treatments 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.

Video Summary

In this presentation, Heather Torbek, a Medical ICU Clinical Pharmacy Specialist, discusses the use of neuromuscular blockers in critically ill patients with acute respiratory distress syndrome (ARDS). She highlights the benefits and risks associated with the use of these drugs, such as improved oxygenation and increased ventilator-free days, but also the potential for adverse effects like ICU-acquired weakness. Torbek emphasizes the importance of limiting neuromuscular blocker exposure and introduces the concept of train-of-four monitoring as a way to achieve this. Train-of-four monitoring involves using a peripheral nerve stimulator to assess the depth of paralysis achieved with neuromuscular blockers. Torbek presents research studies that support the use of train-of-four monitoring to reduce drug exposure and potential harm to patients. She also discusses alternative dosing strategies and the need for individualized approaches to neuromuscular blocker therapy in ARDS patients. Overall, Torbek suggests that a multifaceted approach to neuromuscular blocker management is necessary to minimize adverse effects and improve patient outcomes.

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

neuromuscular blockers

critically ill patients

acute respiratory distress syndrome

train-of-four monitoring

ARDS patients

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.