SCCM Resource Library-49-Evaluation of Dosing Strategies on Cisatracurium on Drug Consumption and Oxygenation

Video Transcription

Hello, everyone. My name is Julie DeBridge and I'm a PGY-1 resident at the University of Pittsburgh Medical Center. Today, I have the pleasure of presenting our research entitled  The Effective Dosing Strategy on Cystatochirium Drug Consumption and Oxygenation in Patients with Acute Respiratory Distress Syndrome. The authors of this presentation have nothing  to disclose. To start some background on everyone's favorite topic, neuromuscular blocking agents such as cystatochirium help to ensure protective lung ventilation by limiting  spontaneous breathing efforts and asynchronous. Current guidelines recommend the use of neuromuscular  blocking agents for patients with ARDS if needed to facilitate protective lung ventilation  but do not make recommendations for a particular dosing scheme. Three separate dosing strategies  for neuromuscular blocking agents have been investigated. The first of which we'll look at include a train-of-four based approach compared to a clinical assessment protocol.  Each of these studies were designed after several case reports were published in the  early 90s suggesting prolonged paralysis associated with a lack of train-of-four monitoring. They  found no difference in cumulative drug exposure or in mean recovery time following paralysis  between groups. The next dosing strategy is that many of you are familiar with. Originally designed by a curiosist to ensure blinding and also utilized in rows with a 15 milligram  bolus dose followed by a flat dose of 37.5 milligram per hour. As these trials are large and randomized, clinicians are often tempted to adopt this dosing strategy. Following the  publication of the accurosist trial, use of a train-of-four based protocol has been evaluated in smaller cohort studies. These two studies found that patients in a fixed dosing arm  received more Sosatricurium at a higher total cost compared to a train-of-four based approach.  Is this still relevant today? A recent survey published in 2020 found that over 96% of academic  intensivists are still utilizing neuromuscular blocking agents for ARDS. There is, however, a discrepancy between dosing approach. 68% of respondents reported that they were using  train-of-four to monitor and adjust neuromuscular blocking agents, a strategy less consistent  with current guidelines, while 21% are titrating to mechanical ventilation goals. Furthermore,  5% are using a fixed dose based on body weight. So which of these approaches should we be using? After the implementation of a ventilator synchrony protocol at our institution, we  sought to answer this question and determine which continuous Sosatricurium dosing strategy utilizes the least amount of drug without compromising efficacy. We conducted a single  center retrospective review of adult patients who received continuous infusions of Sosatricurium  between 2013 and 2018 and had a diagnosis of acute respiratory distress syndrome. Our exclusion criteria is listed on this slide. We looked at cumulative drug consumption within  48 hours and for efficacy, change in P to F ratio from baseline, as well as a secondary marker of gas exchange, change in oxygenation index. The formula to calculate oxygenation  index is listed on this slide for your reference. For our statistical analysis plan, we conducted  a Kruskal-Wallis to compare differences in drug consumption across three groups and a Mann-Whitney-Yu for pairwise comparisons when statistical significance were noted.  We conducted a multivariate linear regression to assess predictors of drug consumption  and for our oxygenation efficacy comparisons, we used two-sided t-tests of equivalence conducted  in a pairwise fashion between three groups to assess similarity of improvement of oxygenation  from baseline. Overall, we included 189 patients with 69 in the ventilator synchrony protocol. This protocol is listed on this slide for your reference. We had 99 patients in our  Trano4 arm and 21 in the fixed dosing arm. Baseline patient characteristics were similar, except for those listed on this slide, including concomitant respiratory disease,  hepatic disease, and those considered to be immunosuppressed.  The use of prone positioning, inhaled epiprocinol, baseline beta-F, and baseline PEEP were also significantly different between groups.  In looking at the infusion titration characteristics, there were significantly more Trano4 charted in the Trano4 protocol compared to the ventilator synchrony group.  Additionally, rate changes also occurred more frequently in our Trano4 group.  The higher number of rate changes in Trano4 checks leads to additional cost, including nursing time, that was not directly captured in our cost comparison in the next slide.  You'll notice the most frequently charted value was the Trano4-004 in the Trano4 group and 404 in the ventilator synchrony group.  Although our ventilator synchrony protocol and Trano4-based protocol had a similar initial rate,  median and max infusion rate were significantly higher in the Trano4 arm.  Overall, we observed almost a 40% reduction in cumulative drug exposure and cost with the ventilator synchrony protocol compared to the TRANO4 protocol. These results were  even more profound when comparing ventilator synchrony protocol to the fixed dosing group.  In our multivariate analysis, only dosing strategy was predictive of total cumulative Cytosaccharidium consumption at 48 hours.  Over time, we observed an improvement in both P to F ratio and oxygenation index with each group.  These results are similar to those previously described in the literature, with an improvement by about 60 in P to F ratio at 48 hours.  On this slide is a graphical representation of the median change in P to F ratio at hours 12 and 24  from baseline, and the results of our t-test of equivalence demonstrated statistical equivalence  at each time point between any group. This is also true for hour 36 and 48.  We observed no difference in hospital length of stay, ICU length of stay, mechanical ventilator time, or in-hospital mortality between groups.  Our study has many strengths to note, the first of which being that this is the largest direct comparison of the three dosing strategies to our knowledge to date. Additionally,  equivalence was evaluated for efficacy at four distinct time points over paralysis,  and also we utilize two markers of oxygenation, including P to F ratio and oxygenation index. Some notable limitations include the retrospective design and the unavoidable  differences in sample size in each protocol. Additionally, the lack of ability to standardize timing of arterial blood gases was a limitation, although we were able to  circumvent this issue by utilizing S to F ratio, which was first used in the ROSE trial.  And lastly, protocol compliance was not assessed.  Following interpretation of these results, we concluded that without impacting efficacy of gas exchange, a protocol using ventilator synchrony for susceptricurium titration  required significantly less drug compared to a trinoforb-based titration and a fixed dosing regimen. Further prospective research, however, is needed to confirm these results.  This work would not have been possible without the tireless support of my mentors and colleagues,  so a huge shout out and thank you to Dr. Grotzinger and Dr. Rivasecki for their mentorship and unwavering support, as well as to the physicians who have  supported us throughout this entire project. Thank you for your time, and I'll now take any questions.  Thank you.

Video Summary

The research presented is about the effective dosing strategy of cystatricurium in patients with acute respiratory distress syndrome (ARDS). The study compared three different dosing strategies: a train-of-four based approach, a clinical assessment protocol, and a fixed dosing regimen. The researchers found that a protocol using ventilator synchrony for cystatricurium titration required significantly less drug compared to the other two strategies, without compromising efficacy in gas exchange. The study also found no difference in hospital length of stay, ICU length of stay, mechanical ventilator time, or in-hospital mortality between the three groups. Further research is needed to confirm these results.

Asset Subtitle

Pharmacology, Pulmonary, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Julie Dibridge

Introduction/Hypothesis: In patients with moderate to severe Acute Respiratory Distress Syndrome (ARDS), guidelines recommend the use of neuromuscular blocking agents (NMBA) but do not make recommendations for a dosing scheme. The optimal strategy to minimize drug exposure, while not compromising efficacy is yet to be clearly established in the literature. Currently, our institution utilizes three different dosing regimens: fixed dose (FD), titration based on train-of-four (TOF), and a ventilator synchrony (VS) protocol. The objective of this study was to determine the effect of dosing strategy on drug consumption and oxygenation in ARDS patients.

Methods: This was a retrospective review of patients with ARDS who received continuous cisatracurium infusion for at least 36 hours between January 2013 and December 2018. Included patients were categorized into one of three dosing strategies (FD, TOF, or VS), as determined by ordered titration parameters. Data were collected from NMBA initiation to the end of paralysis or 48 hours, which ever occurred sooner. The drug utilization outcome was defined as total cisatracurium drug consumption and cost within 48 hours. The efficacy outcome was defined as change in PaO2:FiO2 (PF) and number of spontaneous breaths over the ventilator from baseline to 12, 24, 36 and 48 hours. Categorical data was compared using Chi squared or Fishers exact test as appropriate. Continuous data was compared using Kruskal-Wallis test and Mann-Whitney U test in pairwise fashion. Change in PF ratios were analyzed using T-test of equivalence in a pairwise fashion.

Results: A total of 1078 patients were screened, and 223 patients (FD = 22; TOF = 110; VS = 91) were included. The median infusion rate (mcg/kg/min) was higher in the FD and TOF arm than the VS group: FD 7.5 [IQR 6.7-8.9, p<0.00001], TOF 2.5 [IQR 2-3.5, p<0.0001], VS 1.67 [IQR 1.35-2]. Cost of therapy was higher in the FD and TOF arm than the VS group: FD $4,140, p<0.00001, TOF $1,615, p<0.00001, VS $911. No difference was observed in change in PF ratios or spontaneous breaths over the ventilator.

Conclusions: Without impacting efficacy of gas exchange or ventilator synchrony, the VS protocol required significantly less drug with lower total costs than either TOF or FD protocols. Further prospective research is needed to confirm these results.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Pulmonary

Knowledge Level Advanced

Membership Level Select

Tag Acute Respiratory Distress Syndrome ARDS

Tag Pharmacokinetics Pharmacodynamics

Year 2021

Keywords

cystatricurium

acute respiratory distress syndrome

dosing strategy

ventilator synchrony

gas exchange

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