neuromuscular blockade does not improve mortality in ARDS

Cisatracurium is a benzylisoquinolinium neuromuscular blocking agent (NMBA) that has been tested for clinical benefit in patients with moderate to severe ARDS in two large placebo-controlled randomized clinical trials (RCTs). These RCTs have yielded conflicting results and have not consistently shown lower mortality or faster recovery from respiratory failure (ie, more ventilator-free days).

The ACURASYS and ROSE trials evaluated the benefit of early cisatracurium (within the first 48 h) on mortality rates in moderate to severe ARDS (defined as a PaO2:FiO2 ratio of <150 mm Hg). In ACURASYS, early continuous infusion of cisatracurium decreased 90-day mortality compared with placebo (31% vs 42%), but that finding was not replicated in the ROSE trial (42.5% vs 42.8%; P = ). Taken together, it is not clear that routine, early continuous infusion of cisatracurium for 48 h in isolation has a mortality benefit in moderate to severe ARDS.1 2

Specifically, in ACURASYS trial, while crude 90-day mortality was not significantly lower, 90-day mortality after adjustment for covariates and baseline differences was lower with cisatracurium. Additionally, patients randomized to cisatracurium had more ventilator-free days through day 28 and day 90.

Critics of this trial highlight the remarkably low PEEP used for severe ARDS, delay in separation of survival curves until day 18 (well after the 48 h of cisatracurium), as well as other factors. All patients were deeply sedated regardless of group assignment. Nearly a decade later, the results of the multicenter North American RCT (ROSE) in which 1,006 patients with moderate to severe ARDS (PaO2:FiO2 <150 mm Hg) were randomized to cisatracurium or usual care demonstrated dramatically different results. Virtually identical 90-day mortality rates and ventilator-free day rates were reported for cisatracurium and placebo.

Important differences in patient management between the two trials include use of lighter sedation in the control group of ROSE and higher PEEP in both groups compared with the ACURASYS patients. Additionally, ACURASYS was placebo controlled, while the ROSE control was usual care.

Prolonged weakness after NMBA infusion has been a concern; however, neither RCT demonstrated significant differences in the Medical Research Council muscle strength scale scores with cisatracurium vs placebo. More serious adverse cardiovascular events were seen with cisatracurium than placebo in the ROSE trial. NMBAs with cisatracurium continue to have a role in the management of severe hypoxemic respiratory failure, but the results of these RCTs suggests this should be individualized rather than routine. The role of patient-ventilator dyssynchrony, which might be suppressed with NMBAs, in patient outcome should be examined in future studies that examine the effectiveness of NMBAs on patient outcomes in severe respiratory failure.

Cisatracurium is eliminated by way of Hofmann elimination, a process of nonenzymatic breakdown that is independent of renal and hepatic function and produces no active metabolites. In contrast, the aminosteroid NMBAs pancuronium, vecuronium, and rocuronium undergo hepatic metabolism, with risk for accumulation with advanced liver disease. Furthermore, pancuronium and vecuronium have active metabolites that may accumulate in renal failure. Accordingly, cisatracurium has a more favorable elimination profile than many other NMBAs for use in critically ill patients. The safety and efficacy of cisatracurium for patients with moderate to severe ARDS has been tested in two large multicenter RCTs with conflicting results.345

Footnotes

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  2. 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. PubMed ↩

  3. Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. PubMed ↩

  4. Sessler CN. Counterpoint: should paralytic agents be routinely used in severe ARDS? No. Chest. 2013;144(5):1442-1445. PubMed ↩

  5. Slutsky AS, Villar J. Early paralytic agents for ARDS? Yes, no, and sometimes. N Engl J Med. 2019;380(21):2061-2063. PubMed ↩