ROSE: Neuromuscular Blockers in Early ARDS (2019)

“Among patients with moderate-to-severe ARDS, there was no significant difference in 90-day mortality between patients who received a continuous infusion of cisatracurium and those who were treated with a usual-care approach with lighter sedation targets and no routine neuromuscular blockade.”

  • The PETAL Clinical Trials Network

1. Publication Details

  • Trial Title: Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome
  • Citation: National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008. DOI: 10.1056/NEJMoa1901686
  • Published: May 23, 2019, in The New England Journal of Medicine
  • Author: The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • ARDS, Acute Respiratory Distress Syndrome, Neuromuscular Blockers, Cisatracurium, Mechanical Ventilation, Light Sedation, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with moderate to severe ARDS (Population), does a strategy of early and continuous neuromuscular blockade with cisatracurium (Intervention) compared to a strategy of usual care with light sedation (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The ACURASYS trial (2010) had shown that a 48-hour infusion of cisatracurium improved survival in patients with severe ARDS who were managed with deep sedation. This led to the widespread adoption of this practice in some centers.
  • Knowledge Gap: Since the publication of ACURASYS, the general approach to sedation in the ICU had shifted towards much lighter sedation targets. It was a critical and unanswered question whether the benefits of neuromuscular blockade seen in the context of deep sedation would still be present when compared against a modern strategy of light sedation without routine paralysis.
  • Proposed Hypothesis: The authors hypothesized that a strategy of early neuromuscular blockade would be superior to a light sedation strategy in reducing 90-day mortality in patients with moderate to severe ARDS.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 48 intensive care units (ICUs) in the United States.
  • Trial Period: Enrollment ran from January 2016 to April 2018.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with moderate to severe ARDS (PaO2:FiO2 ratio < 150) who had been intubated for less than 48 hours.
    • Exclusion Criteria: Included severe chronic lung disease, contraindications to neuromuscular blockade, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients were randomized to receive a continuous intravenous infusion of cisatracurium for 48 hours. Sedation was titrated to a goal of deep sedation (RASS -5).
  • Control: Patients were randomized to receive usual care, with a protocolized goal of light sedation (RASS 0 to -1) without the routine use of neuromuscular blockers.
  • Management Common to Both Groups: All patients were managed with a low tidal volume ventilation strategy. Prone positioning was encouraged in both groups for severe ARDS.
  • Power and Sample Size: The authors calculated that a sample size of 1006 patients would provide 90% power to detect an 8.5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included ventilator-free days, ICU and hospital length of stay, and the incidence of serious adverse events.

6. Key Results

  • Enrollment and Baseline: 1006 patients were randomized (501 to the intervention group and 505 to the control group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 209 of 501 patients (42.5%) in the intervention group died, compared with 209 of 505 patients (42.8%) in the control group (p=0.93).
  • Secondary Outcomes: There were no significant differences between the groups in ventilator-free days or length of stay.
  • Adverse Events: The incidence of serious adverse events was similar in both groups. However, patients in the intervention (cisatracurium) group had a higher incidence of cardiovascular events.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.93 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of 48 diverse ICUs make the findings highly generalizable to real-world practice in similar healthcare systems.
  • Statistical Power: The study was large and adequately powered to confidently rule out a modest but clinically important mortality difference.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of critically ill patients with moderate to severe ARDS.
  • Other: A key point for interpretation is that this trial compared two different strategies (paralysis with deep sedation vs. no paralysis with light sedation), not just the effect of the drug itself.

10. Conclusion of the Authors

  • The authors concluded that among patients with moderate-to-severe ARDS, there was no significant difference in 90-day mortality between a strategy of early and continuous neuromuscular blockade and a usual-care approach with lighter sedation targets.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided strong evidence against the routine use of early neuromuscular blockade in all patients with moderate-to-severe ARDS.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with moderate to severe ARDS.
    • Actionable Intervention: The results do not support the routine use of a 48-hour infusion of cisatracurium. A strategy of light sedation without routine paralysis is a safe and effective approach.
  • What This Trial Does NOT Mean: This trial does NOT mean that neuromuscular blockers have no role in ARDS. They remain an important therapy for managing severe patient-ventilator dyssynchrony or for facilitating prone positioning.
  • Implementation Caveats: The key takeaway is that the routine, prophylactic use of neuromuscular blockade for all patients with moderate-to-severe ARDS is not beneficial and may be associated with more cardiovascular side effects.

12. Context and Related Studies

  • Building on Previous Evidence: The ROSE trial (2019) was designed to provide a more definitive answer to the question of neuromuscular blockade in ARDS, particularly in the context of modern, light sedation practices, which was a key difference from the earlier, positive ACURASYS trial (2010) where patients were deeply sedated.
  • Influence on Subsequent Research: The definitive neutral result of this large trial has been highly influential in shaping international ARDS guidelines, which now recommend a more selective, rather than routine, approach to the use of neuromuscular blockers.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is how to best identify the specific subgroup of patients with severe ventilator dyssynchrony who are most likely to benefit from a short course of neuromuscular blockade.
  • Future Directions: Future research is focused on using more advanced monitoring of respiratory mechanics and patient effort to guide a more personalized approach to the use of neuromuscular blockers in ARDS.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, seeking to confirm and generalize the findings of the earlier, influential ACURASYS trial in the context of modern sedation practices.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust. A key strength is that the control arm represented a very high standard of modern ARDS care (light sedation), making the comparison a fair and relevant test of whether neuromuscular blockade adds any benefit on top of this.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of routine neuromuscular blockade in this population.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence that a previously recommended therapy is not beneficial when the standard of care in the control group has evolved and improved.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
Scroll to Top