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Are there data available to support use of fixed-dose cisatracurium for acute respiratory distress syndrome (ARDS)?

Introduction

Acute respiratory distress syndrome (ARDS) is a form of acute lung injury that affects about 10% of hospitalized patients who require critical care.1 Acute respiratory distress syndrome is the most severe form of acute lung injury; it has a mortality rate of around 40%, despite recent treatment advances.1,2 While the definition of ARDS has varied somewhat over time and across different disease state organizations, it is generally defined as a life-threatening condition in which impaired pulmonary gas exchange leads to hypoxemia, hypercapnia, and respiratory acidosis.1,3 The resulting decrease in the circulation of oxygen to tissues throughout the body leads to complications such as inflammation, cell death, organ injury, and organ failure.3 The progression of ARDS involves 3 sequential phases, including an initial exudative phase characterized by clotting within the endothelium and the production of proinflammatory cytokines, followed by a proliferative phase characterized by repair of the alveolar epithelium and extracellular matrix by macrophages, myofibroblasts, and fibroblasts.4 Some patients will further progress to a fibrotic phase in which interstitial and alveolar fibrosis can cause the patient to require extended mechanical ventilation. It can often be difficult to determine the cause of ARDS, but certain indirect and direct risk factors are associated with its development.1 Examples of factors that may function as direct causes of lung injury include pneumonia, inhalation injury, and pulmonary contusion, whereas potential indirect causes of lung injury include sepsis, acute pancreatitis, and cardiopulmonary bypass.

The severity of ARDS can vary significantly; the Berlin Definition provides an established method to diagnose ARDS that can also be used to classify patients as having mild, moderate, or severe disease based on their level of hypoxemia.1,5 All components of the Berlin criteria should be met for a clinical diagnosis of ARDS: acute onset of symptoms within 7 days, the presence of unexplained bilateral opacities on a chest radiograph or computed tomography scan, respiratory failure that cannot be entirely explained by fluid overload or cardiac failure, and impaired oxygenation. The degree of hypoxemia can be used to determine the severity of ARDS through the measurement of the partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio, positive end expiratory pressure (PEEP), and continuous positive airway pressure. Mild ARDS is defined by a PaO2/FiO2 greater than 200 mmHg but not greater than 300 mmHg, moderate ARDS is defined by a PaO2/FiO2 of greater than 100 mmHg but not greater than 200 mmHg, and severe ARDS is defined by a PaO2/FiO2 below 100 mmHg; all 3 categories of ARDS also require a PEEP of at least 5 cmH2O.

Management of ARDS

Lung protective mechanical ventilation (mechanical ventilation using a low tidal volume and low inspiratory pressure) is a mainstay of treatment for ARDS.1,6 Other nonpharmacologic measures, such as increasing PEEP levels on the ventilator, lung recruitment maneuvers, prone positioning, and extra-corporeal membrane oxygenation may also be utilized based on the severity of ARDS; however, evidence supporting these measures is limited. There is limited evidence available on the safety and efficacy of pharmacologic therapies in ARDS; however, treatment of ARDS currently includes therapies such as corticosteroids to potentially decrease the patient’s time on the ventilator and decrease inflammation, fluid management strategies to decrease the length of ventilation, and neuromuscular blocking agents (NMBAs) to reduce the risk of lung injury and decrease patient-ventilator dyssynchrony.1,7

The mechanism of NMBAs in ARDS is not fully understood, but there are several proposed mechanisms through which NMBAs may produce benefits in ARDS patients, including via enhanced respiratory mechanics, improvement in ventilator synchrony to protect the lungs during ventilation, and reduced oxygen consumption.7 The use of NMBAs in ARDS is controversial, since there is a perceived risk of neuromuscular weakness that is associated with their use. Evidence for the efficacy of NMBAs in ARDS is also conflicting; some early studies found that ARDS patients who were given NMBAs had improved oxygenation and a decreased risk of mortality, but other studies have not found the same benefits. However, the existing evidence is also limited by confounding factors such as inclusion of patients with sepsis or patients taking concomitant corticosteroids, and use of a sedative strategy in the control group.  Despite these limitations, NMBAs are still commonly used in the management of ARDS. Cisatracurium is the only NMBA that has been studied for ARDS treatment in randomized controlled trials to date, and it is thought that it may provide an anti-inflammatory benefit in patients with ARDS in addition to the other potential mechanisms of NMBAs.7,8 A set of 3 randomized controlled trials showed that patients with ARDS treated with cisatracurium had an improvement in oxygenation and decreased inflammatory response.9

Guideline Recommendations

Several guidelines have been published the use of NMBAs in various components of critical care, such as ARDS. Two of the most recent guidelines that have been published on the use of NMBAs in ARDS include a 2016 Society of Critical Care Medicine (SCCM) guideline and a 2020 rapid practice guideline.10,11 The 2016 guideline by the SCCM on use of NMBAs in critical care settings recommends administration of NMBAs via continuous intravenous infusion in adults in the early stages of ARDS who have a ratio of PaO2/FiO2 of less than 150 mmHg.10 The guideline rationale further states that infusion of cisatracurium over 48 hours has been shown to reduce the risk of death at 28 days and post-discharge, reduce the risk of barotrauma, and has not been found to contribute to intensive care unit (ICU)-acquired weakness based on the results of a large trial. A recent 2020 rapid practice guideline, formulated by an international panel of 20 clinical experts from 12 countries including the United States and 2 patient representatives, was published on the use of NMBAs in patients with ARDS.11 This guideline recommends lung protective ventilation with infusion of an NMBA for up to 48 hours in adults with moderate to severe ARDS who require continued deep sedation with neuromuscular blockade.

Dosing of cisatracurium for ARDS

The current Food and Drug Administration (FDA)-approved labeling for cisatracurium recommends weight-based dosing of cisatracurium for all indications, including when it is used to facilitate mechanical ventilation in critically ill patients.12 Patients on NMBAs are often monitored using the Train-of-Four (TOF) test to have their cisatracurium doses adjusted.10,13 In TOF monitoring, a nerve simulator is used to deliver an electric current, which causes muscles to twitch based on the strength of the current, location of the test on the body, and the paralysis level.11 Full paralysis is considered to be achieved once the TOF score is zero (number of twitches), and a bolus or dose increase of the continuous cisatracurium infusion is performed when 1 or more twitch responses are observed.13 The accuracy of this method of assessment may be limited by the level of training and experience of staff using the equipment, variations in the technology used to stimulate peripheral nerves, and patient-specific factors, such as presence of hypothermia or edema, which may impact results.10 An additional limitation of TOF monitoring is that it often produces results that vary in different parts of the body and can differ from the results of a clinical evaluation.14

Due to the limitations that are seen with TOF monitoring, there has recently been an increased interest in a fixed-dose approach, which may avoid the limitations seen when dose adjustments are conducted using results from TOF monitoring. A letter to the editor written in 2020 discusses this issue and suggests the use of fixed-dose or “as needed” NMBAs for the shortest interval possible.15 There are no current guideline recommendations on the type of dosing strategy (fixed vs. bolus dosing) that should be used with cisatracurium in patients with ARDS, and there is minimal discussion on cisatracurium dosing strategies across guidelines.10,11 Therefore, the purpose of this FAQ is to review the research that is currently available to support a fixed dosing approach when administering cisatracurium in ARDS.

Literature Review

While clinical practice guidelines do not provide a stance on fixed versus bolus cisatracurium dosing, several clinical trials have been conducted to investigate the variation in outcomes across different cisatracurium dosing strategies.16-20 The studies that are described below in the Table examine the efficacy of fixed-dose administration of cisastracurium in patients with ARDS. The literature includes 3 prospective and 2 retrospective studies; most prospective studies were conducted using an open-label design. Each trial took place in the United States or in France, and most studies were conducted at multiple sites. The enrollment in each study ranged from 30 patients to 1006 patients and was restricted either to patients with severe ARDS or moderate to severe ARDS. The most commonly used fixed dosing strategy across the studies was 37.5 mg/hour of cisatracurium for 48 hours; most studies also allowed for administration of a bolus dose of cisatracurium (usually 15 mg) prior to or at some point after the start of the infusion. Patients who received titration-based doses of cisatracurium typically had their doses adjusted based on their TOF scores, except for 1 study which also included a treatment group with doses adjusted according to a ventilator synchrony protocol (VSP).

In studies that compared different types of dosing strategies, including the fixed-dose, TOF bolus dosing, and VSP strategies, there were generally no statistically significant differences in outcomes such as PaO2/FiO2 ratio, ventilator-free days, and mortality. However, 1 trial did find a statistically significant increase in cisatracurium consumption with a fixed dosing approach compared to patients treated using a TOF-based or VSP strategy, and a second trial found a statistically significant increase in the average cisatracurium dose over 48 hours in patients treated using a fixed dosing strategy compared to patients treated using a TOF-based titration.19,20 Another small randomized controlled trial found that use of fixed-dose cisatracurium led to improvements in some markers of oxygenation, but not others, compared to a control group that did not receive cisatracurium.16 The ACURASYS trial, which compared fixed-dose cisatracurium to placebo, found that patients treated with fixed-dose cisatracurium had significantly more ventilator-free days and a significant reduction in barotrauma compared to patients treated with placebo.18 However, both the intervention and placebo groups were deeply sedated, which could have worsened outcomes in the control group and confounded the findings. The ROSE trial, which included the largest sample size of all of the trials, found no difference in mortality between patients treated with fixed-dose cisatracurium and those treated with usual care with lighter sedation targets; the trial was terminated early due to futility.17 The ROSE trial also found that there was a greater number of serious cardiovascular adverse events in patients treated with fixed-dose cisatracurium, with 14 serious adverse cardiovascular events in the cisatracurium group and 4 serious cardiovascular adverse events in the usual care group. The ACURASYS trial mentioned that bradycardia was seen in 1 patient who received cisatracurium, but that no other adverse events were noted.18 The other studies listed below in the Table did not discuss adverse effects in the patients who were enrolled in the studies.16,19,20 Overall, it is difficult to make firm conclusions from the existing evidence base based on differences among the trials in the study design, patient population included (patients in earlier vs. later stages of ARDS), control groups utilized, and outcomes assessed.

Table. Literature evaluating fixed-dose cisatracurium.16-20
Study design Subjects
InterventionsResults
Prospective trials
Guervilly 201716
 
Prospective RCT conducted in 2 French ICUs		N=30 patients with moderate to severe ARDS within 48 hours of ARDS onsetCIS 15 mg bolus followed by FD CIS 37.5 mg/hour for 48 hours (n=13 with moderate ARDS and n=6 with severe ARDS)


No CIS was administered (n=11)
Patients with moderate or severe ARDS who received CIS infusion had significant increases in the average inspiratory PL (p=0.04) and average expiratory PL (p=0.02), compared to the control group.

Patients who received CIS did not have a change in driving pressure or ∆PL
Moss 201917
 
ROSE trial
 
Multicenter, randomized, unblinded U.S. trial		N=1006 patients with moderate to severe ARDS on mechanical ventilationCIS 15 mg bolus followed by FD CIS 37.5 mg/hour for 48 hours (n=501)


Usual care without a routine NMBA and with lighter sedation targets (n=505)
The trial was terminated early due to futility, which was determined at the second interim analysis
 
The 90-day mortality prior to hospital discharge was similar between groups, with a between-group difference of -0.3% (95% CI, -6.4% to 5.9%; p=0.93)
 
Patients assigned to the intervention group exhibited less physical activity and had a greater incidence of serious cardiovascular adverse events compared to patients in the control group
Papazian 201018
 
ACURASYS trial
 
Prospective, multicenter, double-blind RCT conducted in 20 French ICUs		N=340 patients receiving mechanical ventilation for severe ARDS with an onset within the previous 48 hoursCIS 15 mg bolus followed by FD CIS 37.5 mg/hour for 48 hours (n=178)


Placebo for 48 hours (n=162)


Patients in both groups were deeply sedated prior to administration of the intervention
Patients receiving CIS had a significant decrease in death at 90 days compared to the placebo group (hazard ratio, 0.68; 95% CI, 0.48 to 0.98; p=0.04) after adjusting for baseline PaO2/FiO2 ratio, Simplified Acute Physiology Score IIa, and plateau pressure

The difference in crude 90-day mortality was not significantly different (p=0.08) between groups

The CIS group had significantly more ventilator-free days than the placebo group during the first 28 and 90 days, with 10.6±9.7 days in the CIS group compared to 8.5±9.4 days in the placebo group (p=0.04) in the first 28 days and 53.1±35.8 days in the CIS group compared to 44.6±37.5 days in the placebo group (p=0.03) for the entire 90-day period

Patients treated with FD CIS had significant reductions in barotrauma compared to those treated with placebo (relative risk, 0.43; 95% CI, 0.20 to 0.93; p=0.03)
Retrospective trials
Thompson 202119  
 
Single-center, U.S., retrospective cohort		N=167 adults ≥18 years of age in in a MICU receiving CIS continuous infusion for ≥12 hours for treatment of moderate to severe ARDSFD CIS 37.5 mg/hour (n=126)
 
CIS titrated to TOF (n=41)
 
51.2% of patients in the FD group and 66.7% of patients in the titration group received a bolus dose prior to continuous infusion		Patients on a FD regimen received a significantly higher average dose of CIS over 48 hours (median 2 mcg/kg/min) compared to the titration group (6.4 mcg/kg/min; p<0.001)

No difference in PaO2/FiO2 ratio at 24 and 48 hours, ventilator-free days, mortality, need for bolus NMBA administration, or need for re-initiation of CIS after discontinuation between the FD and titration groups
DiBridge 202120
 
Retrospective review of registry and EMR data		N=189 ICU patients ≥18 years of age with severe ARDSPatients were treated with CIS for ≥36 hoursMedian duration of CIS infusion was significantly shorter in the FD group than in the TOF or VSP groups (48 hours versus 59 hours and 64 hours, respectively; p=0.009)

Overall CIS consumption was lower in the VSP group (415 mg) than the TOF (665 mg) or FD (1730 mg) groups; p<0.001

The change in PaO2/FiO2 ratio from baseline was equivalent among the FD, TOF, and VSP groups at 12, 24, 36, and 48 hours. ICU and hospital length of stay, duration of mechanical ventilation, and mortality were also not different between groups

VSP resulted in equivalent improvement in oxygenation compared to the FD and TOF groups
Abbreviations: ∆PL=inspiratory PL minus expiratory PL; ARDS=acute respiratory distress syndrome; CI=confidence interval; CIS=cisatracurium; EMR=electronic medical record; FD=fixed-dose; FiO2=fractional inspired oxygen; ICU=intensive care unit; MICU=medical intensive care unit; NMBA=neuromuscular blocking agent; PaO2=arterial oxygen partial pressure; PL=transpulmonary pressures; RCT=randomized controlled trial; TOF=train-of-four; U.S.=United States; VSP=ventilator synchrony protocol
a Simplified Acute Physiology Score (SAPS) II: a disease severity score ranging from 0 (least severe) to 163 (most severe) that is generated using 12 physiological measurements taken over 24 hours, information gathered during patient admission, and patient health status information

Conclusions

The current guidelines discussing NMBA use in patients with ARDS do not make specific recommendations as to whether a fixed-dose or titration-based dosing strategy is preferred when administering cisatracurium. There are a few studies available that compare fixed-dose cisatracurium to titration-based approaches, but the literature that is currently available suggests that the outcomes are similar between the 2 strategies. However, a fixed-dose regimen results in significantly greater drug exposure than a dose titration strategy, which may increase the risk of adverse events, particularly cardiac events. The data that are currently available on use of fixed-dose cisatracurium in ARDS have several limitations that could be further explored through additional research utilizing larger, more diverse patient populations and randomized controlled designs.

References

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  2. Qadir N, Chang SY. Pharmacologic treatments for acute respiratory distress syndrome. Crit Care Clin. 2021;37(4):877-893. doi:10.1016/j.ccc.2021.05.009
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  7. Mikkelsen ME, Lanken PN, Christie JD. Acute lung injury and the acute respiratory distress syndrome. In: Hall JB, Schmidt GA, Kress JP. eds. Principles of Critical Care. 4th ed. McGraw Hill; 2014:chap 52. Accessed October 17, 2021. https://accessmedicine.mhmedical.com/content.aspx?bookid=1340&sectionid=80032725
  8. Hraiech S, Yoshida T, Annane D, et al. Myorelaxants in ARDS patients. Intensive Care Med. 2020;46(12):2357-2372. doi:10.1007/s00134-020-06297-8
  9. Szakmany T, Woodhouse T. Use of cisatracurium in critical care: a review of the literature. Minerva Anestesiol. 2015;81(4):450-460.
  10. Murray MJ, DeBlock H, Erstad B, et al. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2016;44(11):2079-2103. doi:10.1097/CCM.0000000000002027
  11. Alhazzani W, Belley-Cote E, Møller MH, et al. Neuromuscular blockade in patients with ARDS: a rapid practice guideline. Intensive Care Med. 2020;46(11):1977-1986. doi:10.1007/s00134-020-06227-8
  12. Nimbex. Prescribing information. AbbVie, Inc.; 2019. Accessed October 23, 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=3db3b76c-3e5a-456e-46a8-456fde1e6195&type=display
  13. Hraiech S, Forel JM, Guervilly C, et al. How to reduce cisatracurium consumption in ARDS patients: the TOF-ARDS study. Ann Intensive Care. 2017;7(1):79. doi:10.1186/s13613-017-0305-2
  14. Bouju P, Tadié JM, Barbarot N, et al. Clinical assessment and train-of-four measurements in critically ill patients treated with recommended doses of cisatracurium or atracurium for neuromuscular blockade: a prospective descriptive study. Ann Intensive Care. 2017;7(1):10. doi:10.1186/s13613-017-0234-0
  15. Quintin L. Neuromuscular blockers in acute respiratory distress syndrome: flat dose or not. Are we missing the point?. Crit Care Med. 2020;48(5):e438. doi:10.1097/CCM.0000000000004280
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  17. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, et al. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med. 2019;380(21):1997-2008. doi:10.1056/NEJMoa1901686
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  19. Thompson Bastin ML, Smith RR, et al. Comparison of fixed dose versus train-of-four titration of cisatracurium in acute respiratory distress syndrome. J Crit Care. 2021;65:86-90. doi:10.1016/j.jcrc.2021.05.011
  20. DiBridge JN, Rivosecchi RM, McVerry BJ, Lamberty PE, Donahoe MP, Groetzinger LM. Comparison of three cisatracurium dosing strategies in acute respiratory distress syndrome: A focus on drug utilization and improvement in oxygenation. J Crit Care. 2021;66:166-172. doi:10.1016/j.jcrc.2021.07.012

Prepared by:
Nicole Szydlowski
PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

November 2021

The information presented is current as of October 5, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.