ACURASYS: Neuromuscular Blockers in Early ARDS (2010)

“Early administration of a neuromuscular blocking agent for 48 hours in patients with severe ARDS improved the adjusted 90-day survival and increased the number of ventilator-free days without increasing muscle weakness.”

  • The ACURASYS Study Investigators

1. Publication Details

  • Trial Title: Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome
  • Citation: Papazian L, Forel JM, Gacouin A, et al. Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome. N Engl J Med. 2010;363(12):1107-1116. DOI: 10.1056/NEJMoa1005372
  • Published: September 16, 2010, in The New England Journal of Medicine
  • Author: Laurent Papazian, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • ARDS, Mechanical Ventilation, Neuromuscular Blockers, Cisatracurium, Patient-Ventilator Synchrony

3. The Clinical Question

  • In adult patients with severe ARDS (Population), does early administration of a 48-hour infusion of a neuromuscular blocking agent (NMBA) (Intervention) compared to placebo (Comparison) improve 90-day survival (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Achieving effective lung-protective ventilation in severe ARDS can be difficult due to patient-ventilator dyssynchrony (when the patient “fights” the ventilator). NMBAs were known to improve synchrony and oxygenation, but there were significant concerns that they could cause prolonged, profound muscle weakness (ICU-acquired weakness).
  • Knowledge Gap: It was unknown if the potential benefits of improved patient-ventilator synchrony from a short course of NMBAs outweighed the potential harm of muscle weakness in patients with severe ARDS.
  • Proposed Hypothesis: The authors hypothesized that a 48-hour infusion of an NMBA in early, severe ARDS would improve survival without increasing the risk of muscle weakness.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 20 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from March 2006 to March 2008.
  • Population:
    • Inclusion Criteria: Adult patients intubated for less than 48 hours with severe ARDS, defined as a PaO2:FiO2 ratio of <150 on a PEEP of ≥5 cm H2O and a tidal volume of 6-8 ml/kg.
    • Exclusion Criteria: Included contraindications to NMBAs, pregnancy, chronic respiratory failure, and expected duration of ventilation <48 hours.
  • Intervention: Patients received a 48-hour continuous infusion of cisatracurium.
  • Control: Patients received a matching placebo infusion for 48 hours.
  • Management Common to Both Groups: All patients were deeply sedated and managed with a standardized lung-protective ventilation protocol.
  • Power and Sample Size: The authors calculated that a sample of 340 patients would provide 80% power to detect a 15% absolute difference in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The proportion of patients who died before hospital discharge or at 90 days, adjusted for baseline risk factors.
    • Secondary Outcomes: Included 28-day mortality, ventilator-free days, organ-failure-free days, barotrauma, and ICU-acquired weakness.

6. Key Results

  • Enrollment and Baseline: 340 patients were randomized (178 to cisatracurium and 162 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The adjusted 90-day mortality was significantly lower in the cisatracurium group. The hazard ratio for death at 90 days was 0.68 (95% CI, 0.48 to 0.98; p=0.04).
  • Secondary Outcomes: The crude (unadjusted) 90-day mortality was also lower in the cisatracurium group (31.6% vs. 40.7%; p=0.08), as was 28-day mortality (23.7% vs 33.3%; p=0.05). The cisatracurium group had more ventilator-free days and organ-failure-free days.
  • Adverse Events: The study monitored for ICU-acquired weakness as a key safety outcome. There was no significant difference in the incidence of ICU-acquired weakness between the two groups (assessed in patients who stayed in the ICU for more than 7 days). The rate of barotrauma was lower in the cisatracurium group.

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 Cox proportional-hazards model, adjusted for baseline covariates.
  • Primary Outcome Analysis: The primary outcome was a time-to-event analysis of 90-day mortality.
  • Key Statistic(s) Reported: Adjusted Hazard Ratio for death at 90 days: 0.68 (95% CI, 0.48 to 0.98; P-value: 0.04).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the adjusted result as 0.68.
      • Clinical Meaning: The HR of 0.68 means that patients in the cisatracurium group had a 32% lower risk of dying at any given time point over 90 days compared to the placebo group, after adjusting for baseline differences.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.48 to 0.98.
      • Clinical Meaning: Since this range is entirely below 1.0, it confirms that the result is statistically significant.
    • P-value: The p-value of 0.04 is below the 0.05 threshold, indicating the result is statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (unadjusted 90-day mortality):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 40.7% – 31.6% = 9.1%.
      • Clinical Meaning: For every 100 patients with severe ARDS treated with this protocol, about 9 additional deaths were prevented at 90 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.091 = 11.
      • Clinical Meaning: You would need to treat 11 patients with a 48-hour cisatracurium infusion to prevent one additional death.
  • Subgroup Analyses: No significant subgroup analyses were reported.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing selection and performance bias, leading to a high degree of internal validity.
  • Generalizability: The inclusion of 20 centers increases the external validity of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is robust and highly relevant.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): All patients were deeply sedated, so the results may not apply to patients managed with lighter sedation strategies. The benefit was seen in patients with severe ARDS (mean PaO2:FiO2 of ~100), and may not apply to those with milder ARDS.
  • Other: The primary outcome was an adjusted analysis, and the unadjusted mortality difference did not reach statistical significance (p=0.08), though it trended in the same direction.

10. Conclusion of the Authors

  • In patients with severe ARDS, early administration of a 48-hour infusion of cisatracurium improved 90-day survival and increased the time off the ventilator, without increasing the risk of muscle weakness.

11. To Summarize

  • Impact on Current Practice: This trial provided strong evidence that a short course of neuromuscular blockade is not only safe but also beneficial in early, severe ARDS. It has led to the widespread adoption of this practice as part of the management of the sickest ARDS patients.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe ARDS (PaO2:FiO2 < 150) within the first 48 hours of their illness.
    • Actionable Intervention: Consider a 48-hour continuous infusion of a neuromuscular blocking agent (e.g., cisatracurium).
    • Expected Benefit: This intervention can be expected to prevent approximately one death for every 11 patients treated.
  • What This Trial Does NOT Mean: This trial does not mean that all patients with ARDS should receive neuromuscular blockers, nor does it support prolonged use beyond 48 hours.
  • Implementation Caveats: This strategy should be used in conjunction with a deep sedation strategy to ensure patient comfort and amnesia.

12. Context and Related Studies

  • Building on Previous Evidence: The ACURASYS trial (2010) was the first large RCT to show a mortality benefit for NMBAs in ARDS, addressing a long-standing clinical question.
  • Influence on Subsequent Research: The positive findings of this trial were later challenged by the ROSE trial (2019), which did not find a benefit for NMBAs in a similar patient population. This has led to an ongoing debate about which patients benefit most and whether the deep sedation used in ACURASYS was a key factor in its success.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is why the ROSE trial failed to replicate these positive findings. Differences in sedation depth, PEEP strategies, and patient populations between the two trials are all potential explanations.
  • Future Directions: Future research is focused on identifying which specific ARDS patients (e.g., those with severe ventilator dyssynchrony) are most likely to benefit from neuromuscular blockade.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and important clinical dilemma with a clear risk-benefit trade-off.
  • Methods: The study design was excellent (multicenter, double-blind RCT). The specific inclusion of a systematic assessment for ICU-acquired weakness was a major strength.
  • Results: The study found a statistically significant benefit in its primary, adjusted outcome. While the unadjusted mortality benefit was not statistically significant, the consistent positive signals across multiple important secondary outcomes (ventilator-free days, barotrauma) strengthen the conclusion.
  • Conclusions and Applicability: The authors’ conclusion is a fair interpretation of the data. The subsequent neutral ROSE trial (2019) has made the applicability of these findings a subject of intense debate. The results of ACURASYS are likely most applicable to patients with severe ARDS who are managed with a deep sedation strategy, as was done in this trial.

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.
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