Neuromuscular Blockade in Early Acute Respiratory Distress Syndrome (ARDS)

Summary

·         Cisatracurium besylate is indicated as an adjunct to general anesthesia to facilitate tracheal intubation, and it is also indicated for mechanical ventilation in ICU patients.1

·         Dosing varies widely and dosage forms include injections as single-dose vials or multi-dose vials.1

·         A multi-center, randomized, placebo controlled, double-blind study, written by Moss M. et. al., looked at a sample of 340 patients in the ICU with severe ARDS who were either assigned cisatracurium besylate or placebo. This study determined that the hazard ratio for mortality at 90 days in the cisatracurium group versus placebo was 0.68, and secondary outcomes such as ventilator free days, days free of organ failure, and days spent outside the ICU were significantly superior within the cisatracurium group compared to placebo.2

·         Findings conclude that in patients with severe ARDS, when compared to placebo, the cisatracurium group had significantly less primary and secondary outcomes including overall death, ventilator free days, and more days free of organ failure.2

Clinical Data

Study Design

A multi-center, randomized, placebo controlled, double-blind study, was conducted by authors Moss M. et. al., in France from March 2006 through March 2008.2 The purpose of this study was to assess whether a short term treatment course with a neuromuscular blocking agent, cisatracurium, in early severe ARDS would improve clinical outcomes.2 Some pertinent inclusion criteria for the participants in this study included receipt of endotracheal mechanical ventilation for ARDS, and the presence of a variety of factors indicating severe ARDS for no longer than 48 hours, and absence of clinical evidence of left atrial hypertension.2 Patients were randomly assigned to either cisatracurium or placebo.2 Of the 340 patients in the ICU with severe ARDS, 178 were assigned to cisatracurium, and 162 were assigned to placebo.2 Follow-up was conducted daily for 90 days. The cisatracurium was a 150 mg formulation and the recommended dosing was a 3-ml rapid intravenous infusion of 15 mg of cisatracurium besylate or placebo, followed by a continuous infusion of 37.5 mg per hour for 48 hours.2

An open-label, rapid, intravenous injection of 20 mg of cisatracurium was allowed in both groups if the end-inspiratory plateau pressure remained greater than 32 cm of water for at least 10 minutes despite the administration of increasing doses of sedatives and decreasing tidal volume and positive end-expiratory pressure (if tolerated).2 The study was powered at 80% and the differences between the groups was assessed using Student’s t-test, the Wilcoxon test, the chi-square test, or Fisher’s exact test, as appropriate. 2 A Kaplan Meier curve was used to assess the time from enrollment to death and time to disconnection from the ventilator for at least 48 hrs. 2 The primary endpoint being evaluated was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e. 90-day in-hospital mortality rate).2 Secondary outcomes included 28 day mortality, number of days outside the ICU between days 1 and 28 AND between days 1 and 90, # of days without organ or system failure between days 1 and 28, newly developed barotrauma, and number of ventilator free days between days 1 and 28 AND between days 1 and 90.2

Results

Based on Figure 2 (shown below), the hazard ratio for death at 90 days in cisatracurium vs placebo was 0.68 with a 95% CI of 0.48 to 0.98. 2 This indicates that the cisatracurium group showed a 32% reduction in death compared to placebo which was a statistically significant finding. This finding also had a p-value of 0.04 which indicated significance as well. As for the secondary outcomes, results can be seen in Table 3. 2 The cisatracurium group had significantly more ventilator free days than placebo (both at 28 and 90 days), significantly more days free of organ failure compared to placebo, significantly more days spent outside the ICU between day 1 and 90, and significantly less incidences of barotrauma and pneumothorax compared to placebo. 2 This can be seen correspondingly with significant p-values for each of the secondary outcomes all within Table 3. 2 These findings determined that significantly improved clinical outcomes were seen in the cisatracurium group compared to the placebo group.

Safety

The only adverse event reported in this study was bradycardia which had developed in one patient that was randomized to the cisatracurium group. No additional adverse event data were reported in this study.
Pertinent Data
Figure 2. Kaplan-Meier Estimates of the Probability of 90 Day Survival.

Table 3. Secondary Outcomes.

References

1.      Nimbex (cisatracurium besylate). [package insert]. North Chicago, IL. Abbvie. Approved in 1995. Accessed on Oct. 9, 2020.

2.      Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. doi: 10.1056/NEJMoa1005372. PMID: 20843245.