No mortality benefit with early neuromuscular blockade in ARDS
Early neuromuscular blockade (NMB) with concomitant heavy sedation in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) did not result in a significant mortality difference vs usual care, the ROSE* trial has shown.
At 90 days, 42.5 percent of patients in the intervention group and 42.8 percent in the usual care group died before hospital discharge (between-group difference, -0.3 percent, 95 percent confidence interval [CI], -6.4 to 5; p=0.93). [N Engl J Med 2019;doi:10.1056/NEJMoa1901686]
“The results are relevant for contemporary practice,” said lead author Professor Derek Angus from the Department of Critical Care Medicine, University of Pittsburgh in Pittsburgh, Pennsylvania, US. “The clinical implications could be wide-reaching as this will immediately clarify current guidelines regarding the role of continuous infusions of NMB, which we now think need not be used.”
ROSE investigators sought to assess the efficacy and safety of a 48-hour continuous infusion of the neuromuscular blocker cisatracurium with concomitant deep sedation vs usual care with light sedation and without routine NMB in 1,006 patients enrolled at a median of 7.6 hours after onset of moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water).
Outcomes were reported at ATS 2019.
Results not ROS(E)y for heavy sedation strategy
“Systematic early commitment to a continuous infusion of NMB with heavy sedation to all patients does not confer any advantage over a strategy that emphasizes light sedation whenever possible, only giving short boluses of NMB and sedation when absolutely necessary,” Angus said.
Patients (mean age 55 years) were randomized to intervention (n=501) or usual-care approach (n=505). Most of them were men, and nearly three-quarters were Caucasians. The primary cause of lung injury was pneumonia. At 90 days, the primary endpoint of in-hospital death from any cause was almost identical in both groups (p=0.93).
At 28 days, no between-group differences were seen in the secondary endpoints of in-hospital mortality, days free of ventilation, days out of the ICU, or days out of the hospital. The trial was stopped early for futility at the second interim analysis.
“We aimed to enrol 1,400 patients, but at the second interim analysis, with roughly 1,000 patients enrolled, we had our answer. NMB was not superior to light sedation,” Angus said.
In terms of safety, incidence of recall of paralysis, barotrauma, and pneumothorax was similar between the intervention and the usual care groups. Rate of serious adverse events was higher with the intervention group (35 vs 22; p=0.09), so were serious cardiovascular events (14 vs 4; p=0.02). However, new-onset atrial fibrillation (AF) and supraventricular tachycardia were comparable between groups.
There were no consistent differences in endpoints assessed at 3, 6, and 12 months, including survival, disability, cognitive function, return to work, health-related quality of life, patient-reported health, pain interference, and symptoms of post-traumatic stress.
ROSE vs ACURASYS: Results differ
Angus said it was important to re-examine early NMB with concomitant heavy sedation in ROSE because the original trial ACURASYS** compared NMB to a control arm that is “different from the control care we would give today.”
“In ACURASYS, the intervention was NMB with heavy sedation vs a control arm that used heavy sedation alone,” Angus said. “Current practice is to promote light sedation, whenever possible. In ROSE, we compared the same intervention — NMB plus heavy sedation — to a different control arm using light sedation targets.”
ROSE was larger than ACURASYS, and its results were markedly different from those of the ACURASYS, said Drs Arthur Slutsky and Jesús Villar, both from Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital in Toronto, Ontario, Canada, in an accompanying editorial. [N Engl J Med 2019;doi:10.1056/NEJMe1905627]
In the ROSE trial, mortality at 90 days was nearly identical in the two groups (42.5 percent for intervention vs 42.8 percent for control) and there was no between-group difference in barotrauma. In ACURASYS, 48 hours of deep sedation with muscle paralysis induced by cisatracurium improved 90-day survival and increased ventilator time-off without increasing muscle weakness. [N Engl J Med 2010;16;363:1107-1116]
The difference in sedation levels between trials could have been a major reason for the difference in findings, said the editorialists.
NBM not for all patients, then, for whom?
Findings from ROSE suggest that patients with moderate-to-severe ARDS should not be treated routinely with early NMB, said Slutsky and Villar. However, there is a rationale for NMB in patients, who, despite carefully implemented ventilatory and sedation strategies, demonstrate a ventilatory pattern that confers a predisposition to ventilator-induced lung injury, in those with increased respiratory drive that could generate potentially injurious transpulmonary pressure swings, or in patients with ventilator dyssynchrony, they added.
All things considered, therapeutic strategies in ARDS should be tailored to the underlying disease or injury mechanism at any point in time, rather than being applied uniformly to all ARDS patients, the editorialists concluded.