Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome

Abstract

Background: The benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear.

Methods: We randomly assigned patients with 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) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days.

Results: The trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, -0.3 percentage points; 95% confidence interval, -6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months.

Conclusions: Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.).

Figure 1.. Patient Screening, Enrollment, and Follow-up.

Patients may have had more than one reason for exclusion. Two patients were randomly assigned twice to the control group. No patients were lost to follow-up. NMB denotes neuromuscular blockade, and Pao2:Fio2 the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen.

Figure 2.. Neuromuscular Blockade and Sedation.

Panel A shows the mean percentage of patients who received continuous neuromuscular blockade, and Panel B shows the mean percentage of patients who were under light sedation during the first week of the trial. Light sedation was defined by a score of 0 or −1 on the Richmond Agitation–Sedation Scale (scores range from 4 [combative] to −5 [unresponsive], with a score of 0 indicating that the patient is alert and calm), a score of 3 or 4 on the Riker Sedation–Agitation Scale (scores range from 1 [unresponsive] to 7 [dangerous agitation], with a score of 4 indicating that the patient is calm and cooperative), or a score of 2 or 3 on the Ramsay Sedation Scale (scores range from 1 [anxious, restless] to 6 [unresponsive], with a score of 2 indicating that the patient is cooperative and oriented).^– More details are provided in Tables S3 and S4 in the Supplementary Appendix. I bars indicate standard errors.

Figure 3.. Patients Who Survived to Hospital Discharge and Were Discharged Home during the First 90 Days after Randomization.

The period of hospitalization included transfer to other health care facilities.