Objectives

To determine the efficacy and safety of early neuromuscular blockade with concomitant heavy sedation as compared with a strategy of usual care with lighter sedation targets in patients with moderate-to-severe ARDS.

Background

It has been well established that the approaches used for the application of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) can affect survival and outcomes after discharge from the intensive care unit (ICU). A large, multicenter trial conducted a decade before this study reported that the early administration of a 48-hour infusion of neuromuscular blockade in patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen [Pao2] to the fraction of inspired oxygen [Fio2] of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥5 cm of water) resulted in lower mortality than a strategy of deep sedation without routine neuromuscular blockade. Despite these encouraging results, early neuromuscular blockade has not been widely adopted. Potential concerns include the lack of research comparing neuromuscular blockade and deep sedation with current practice (which promotes lighter sedation targets) as well as limited data on the effect of neuromuscular blockade on neuromuscular function and other long-term outcomes. Therefore, the PETAL-ROSE study was initiated to determine the efficacy and safety of early neuromuscular blockade with concomitant heavy sedation as compared with a strategy of usual care with lighter sedation targets.

Subjects

Eligible participants were adults undergoing mechanical ventilation through an endotracheal tube and who had the presence of all the following conditions for less than 48 hours: PaO2/FiO2 < 150 mm Hg with a PEEP of ≥ 8 cm of water, bilateral pulmonary opacities not explained by effusions or lung collapse, and respiratory failure not explained by cardiac failure or fluid overload.

1006 participants were enrolled. 501 participants were randomly assigned to the intervention group, and 505 participants were randomly assigned to the control group.

Design

PETAL-ROSE was a multicenter, unblinded, randomized trial of patients with moderate-to-severe ARDS. Participants were randomly assigned in a 1:1 ratio to receive 48 hours of continuous neuromuscular blockade with concomitant deep sedation (intervention group) or to receive usual care without routine neuromuscular blockade and with lighter sedation targets (control group).

Patients in the intervention group who were not under deep sedation at baseline were deeply sedated within 4 hours after randomization. Subsequently, patients in this group received an intravenous bolus of 15 mg of cisatracurium, followed by a continuous infusion of 37.5 mg per hour for 48 hours. After the 48-hour trial intervention period, decisions regarding further use of neuromuscular blockade, including the choice of agent, were left to the discretion of the treating clinician. Neuromuscular blockade could be stopped early if the patient met the criteria for freedom from mechanical ventilation (Fio2 ≤0.40 and PEEP ≤8 cm of water) for at least 12 hours.

All patients were treated with a strategy of low tidal volume ventilation within 2 hours after randomization and a high PEEP strategy for up to 5 days after randomization. Assessors who were unaware of the group assignment interviewed surviving patients or their proxies at 3, 6, and 12 months after randomization.

The primary end point was in-hospital death from any cause at 90 days (in-hospital was defined as the time in the trial hospital plus transfer to another hospital, including the time in long-term acute care facilities).

Conclusions

After the second interim analysis, the decision to stop the trial for futility was made independently by the data and safety monitoring board.

In critically ill patients identified shortly after the diagnosis of moderate-to-severe ARDS, the addition of early continuous neuromuscular blockade with concomitant deep sedation did not result in lower mortality than a usual-care approach to mechanical ventilation that included lighter sedation targets.

National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, 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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