The New England Journal of Medicine MAY 19, 2019

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome

The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network (Derek C. Angus, et al.)

Bottom Line

The ROSE trial found that a strategy of early continuous neuromuscular blockade with concomitant deep sedation did not result in a significant mortality difference at 90 days compared with a usual-care strategy emphasizing light sedation in patients with moderate-to-severe ARDS.

Key Findings

1. The primary endpoint of 90-day in-hospital mortality was nearly identical between groups, occurring in 42.5% of the intervention group and 42.8% of the control group (P = 0.93).

2. The trial was terminated early for futility at the second interim analysis, as the intervention failed to demonstrate superiority.

3. Patients in the neuromuscular blockade arm experienced a higher incidence of serious cardiovascular adverse events (e.g., arrhythmias) compared to the control group (14 vs 4 events, P = 0.02).

4. Secondary clinical outcomes, including 28-day mortality, ventilator-free days, and ICU-free days, showed no statistically significant differences between the two strategies.

Study Design

Design

RCT

Open-Label

Sample

1,006

Patients

Duration

90 days

Median

Setting

Multicenter, US

Population Adult patients with moderate-to-severe ARDS (PaO2:FiO2 < 150 mm Hg with PEEP ≥ 8 cm of water) enrolled shortly after intubation.

Intervention 48-hour continuous infusion of cisatracurium with deep sedation.

Comparator Usual care without routine neuromuscular blockade and with lighter sedation targets.

Outcome In-hospital death from any cause at 90 days.

Study Limitations

• The trial was unblinded, which could introduce bias in the management of sedation and co-interventions.

• The control arm involved a 'usual-care' approach with lighter sedation targets; however, deviations in sedation depth and the occasional use of rescue neuromuscular blockade in the control group may have minimized potential treatment effects.

• The trial was stopped early for futility, which may limit the precision of secondary outcome assessments.

• The lower rate of prone positioning used in this trial compared to more contemporary standards of care might affect the generalizability of the findings to current practice.

Clinical Significance

These findings suggest that routine early neuromuscular blockade is not required for patients with moderate-to-severe ARDS when managed with modern, lung-protective ventilation and light sedation strategies, challenging the prior paradigm set by the 2010 ACURASYS trial.

Historical Context

The ACURASYS trial (2010) previously suggested a 90-day survival benefit with early neuromuscular blockade in severe ARDS. However, that trial utilized different ventilation protocols and higher sedation targets. The ROSE trial was designed to re-evaluate this strategy within the context of contemporary clinical care, which prioritizes lower tidal volumes, higher PEEP, and lighter sedation.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale for using neuromuscular blocking agents (NMBAs) in the management of moderate-to-severe ARDS, and how does this relate to the concept of 'VILI' (Ventilator-Induced Lung Injury)?

Key Response

NMBAs are used to eliminate patient-ventilator dyssynchrony, which can cause 'pendelluft' (internal redistribution of gas to dependent lung zones) and high transpulmonary pressures. By paralyzing the diaphragm and chest wall, NMBAs ensure the ventilator delivers consistent, lung-protective volumes, thereby reducing barotrauma, volutrauma, and biotrauma—collectively known as VILI.

Resident

The ROSE trial compared early neuromuscular blockade to a 'usual care' strategy. What were the defining characteristics of this 'usual care' arm, and why did this choice of control lead to different conclusions than the earlier ACURASYS trial?

Key Response

The ROSE control group emphasized a light sedation strategy (maintaining a RASS of -1 to 0), whereas the earlier ACURASYS trial (which showed NMB benefit) used deeper sedation in its control group. ROSE suggests that when patients are kept lightly sedated, the routine addition of paralysis provides no extra survival benefit, whereas paralysis may have only looked superior in ACURASYS because it mitigated the harms of deep sedation and less lung-protective ventilation.

Fellow

Given that the ROSE trial allowed for 'rescue' neuromuscular blockade in the control group, how should a clinician interpret the 17% crossover rate when applying these results to a patient with refractory hypoxemia and a P/F ratio < 100?

Key Response

The 17% crossover rate for rescue paralysis in the control arm reflects 'pragmatic' trial design but can dilute the treatment effect toward the null. Fellows must recognize that ROSE does not advocate against NMB in all cases; rather, it indicates that routine, early NMB is not superior to a strategy of light sedation with NMB reserved for specific clinical triggers like refractory hypoxemia or severe dyssynchrony.

Attending

In the post-ROSE trial era, how should the hierarchy of interventions for moderate-to-severe ARDS (P/F < 150) be prioritized during bedside rounds, specifically regarding the timing of prone positioning versus NMB initiation?

Key Response

Evidence for prone positioning (PROSEVA) remains robust for mortality benefit, whereas the evidence for NMB is now neutral (ROSE). Therefore, the teaching priority should be early prone positioning as a primary intervention, while NMB should be viewed as a supportive tool to achieve ventilation goals or as a rescue for dyssynchrony, rather than a mandatory co-intervention for all ARDS patients.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ROSE trial was terminated early for futility. Discuss the impact of this early termination on the power of the study to detect a small but clinically significant treatment effect (e.g., a 3-5% absolute mortality reduction) and the precision of the resulting confidence intervals.

Key Response

Stopping for futility occurs when the conditional power to reach a statistically significant result is very low. While it prevents wasting resources, it often results in wider confidence intervals that may still include clinically meaningful differences. In ROSE, the 95% CI for the 90-day mortality difference ranged from -6.4 to 5.9 percentage points, meaning a small benefit or harm cannot be entirely ruled out by the data.

Journal Editor

As a peer reviewer, how would you evaluate the internal validity of the ROSE trial considering the lack of blinding, and what specific measures did the investigators take to mitigate the risk of performance bias?

Key Response

Blinding is impossible with NMBAs due to the obvious clinical effect. This introduces risk of performance bias (e.g., clinicians managing the control group differently). To mitigate this, the ROSE investigators used a standardized protocol for the 'usual care' arm (light sedation targets) and utilized a primary outcome (90-day mortality) that is objective and less susceptible to observer bias than subjective clinical scores.

Guideline Committee

Should the ROSE trial findings prompt a change in the 'weak recommendation' for NMB in ARDS found in the 2017 ATS/ESICM guidelines, and how should 'standard of care' be redefined regarding sedation depth?

Key Response

The 2017 guidelines 'suggested' NMB based on ACURASYS. ROSE provides high-certainty evidence that routine NMB plus deep sedation is not superior to light sedation without routine NMB. Future guidelines should likely downgrade the recommendation to 'conditional' or 'only for specific indications' (like dyssynchrony), while simultaneously strengthening the recommendation for light sedation (RASS -1 to 0) as the primary standard of care in the control of ARDS.

Clinical Landscape

Noteworthy Related Trials

2000

ARMA Trial

n = 861 · NEJM

Tested

Low tidal volume ventilation (6 mL/kg PBW)

Population

Patients with acute lung injury and ARDS

Comparator

Traditional tidal volume ventilation (12 mL/kg PBW)

Endpoint

Mortality

Key result: Low tidal volume ventilation significantly reduced mortality and the number of ventilator-free days compared to traditional ventilation.

2010

ACURASYS Trial

n = 340 · NEJM

Tested

Cisatracurium besylate

Population

Patients with severe ARDS (PaO2/FiO2 < 150)

Comparator

Placebo

Endpoint

90-day mortality

Key result: Early administration of a neuromuscular blocking agent improved 90-day survival and increased ventilator-free days.

2013

PROSEVA Trial

n = 466 · NEJM

Tested

Prone positioning

Population

Patients with severe ARDS

Comparator

Supine positioning

Endpoint

28-day mortality

Key result: Early application of prone positioning in patients with severe ARDS resulted in significantly lower 28-day and 90-day mortality.

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