Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome

Authors: Laurent Papazian, M.D., Ph.D.; Jean-Marie Forel, M.D.; Arnaud Gacouin, M.D.; Christine Penot-Ragon, Pharm.D.; Gilles Perrin, M.D.

Journal: The New England Journal of Medicine

Year: 2010

Volume: 363

Issue: 12

Type of Study: Multicenter, Double-Blind, Randomized Controlled Trial

DOI/PMID: ClinicalTrials.gov number, NCT00299650

Quick Reference Summary

Key Findings: Early administration of cisatracurium besylate in patients with severe ARDS significantly reduced the adjusted 90-day mortality rate (hazard ratio, 0.68; 95% CI, 0.48–0.98; P=0.04) compared to placebo. Additionally, cisatracurium increased ventilator-free days without increasing the incidence of ICU-acquired paresis.

Primary Outcome Measures: 90-day in-hospital mortality was reduced from 40.7% in the placebo group to 31.6% in the cisatracurium group (absolute risk reduction of 9.1 percentage points).

Core Clinical Question

In adults with early severe acute respiratory distress syndrome (ARDS) undergoing mechanical ventilation, does treatment with the neuromuscular blocking agent cisatracurium besylate for 48 hours improve 90-day mortality compared to placebo?

Background

Disease Overview: Acute Respiratory Distress Syndrome (ARDS) is characterized by acute hypoxemic respiratory failure, affecting medical and surgical patients, with a high mortality rate ranging from 40% to 60%.

Prior Data: Neuromuscular blocking agents may improve oxygenation and reduce ventilator-induced lung injury. Previous studies suggested potential benefits of neuromuscular blockers in ARDS but were not adequately powered to assess mortality.

Current Standard of Care: Lung-protective mechanical ventilation using low tidal volumes (6-8 ml/kg of predicted body weight) to minimize ventilator-induced lung injury.

Knowledge Gaps Addressed by Study: The impact of early neuromuscular blockade on long-term mortality in severe ARDS. Balancing potential benefits in oxygenation and ventilation with risks of muscle weakness.

Study Rationale: To evaluate whether early use of cisatracurium besylate can improve survival and clinical outcomes in severe ARDS patients receiving lung-protective ventilation.

Methods Summary

Study Design: Multicenter, double-blind, randomized, placebo-controlled trial.

Setting and Time Period: Conducted in 20 Intensive Care Units (ICUs) across France from March 2006 to March 2008.

Population Characteristics: 340 patients with early severe ARDS (onset within 48 hours) requiring mechanical ventilation.

Inclusion Criteria:

• Age ≥18 years.
• Acute hypoxemic respiratory failure with PaO₂:FiO₂ ratio <150.
• Positive end-expiratory pressure (PEEP) ≥5 cm H₂O.
• Tidal volume of 6-8 ml/kg of predicted body weight.

Exclusion Criteria: Continuous neuromuscular blocker infusion at enrollment, pregnancy, severe chronic respiratory or liver disease, recent enrollment in another trial, etc.

Intervention Details: Cisatracurium besylate administered as a 15 mg IV bolus followed by a continuous infusion of 37.5 mg per hour for 48 hours.

Control/Comparison Group: Placebo administered in identical 30-ml vials for intravenous infusion.

Primary Outcome: 90-day in-hospital mortality, adjusted for baseline PaO₂:FiO₂ ratio and plateau pressure using a Cox proportional hazards model.

Secondary Outcomes: 28-day mortality, ventilator-free days, ICU-free days, organ-failure-free days, and incidence of ICU-acquired paresis.

Statistical Analysis Approach: Kaplan–Meier survival curves, Cox regression with adjustment for predefined covariates, intention-to-treat analysis.

Sample Size Calculations: Based on anticipated 50% mortality in placebo group and a 15% absolute reduction in mortality with 80% power and α=0.05, requiring 340 patients.

Ethics and Funding Information: Approved by the ethics committee of Assistance Publique–Hôpitaux de Marseille and conducted in accordance with French law. Funded by Assistance Publique–Hôpitaux de Marseille, French Ministry of Health, and GlaxoSmithKline.

Detailed Results

Participant Flow and Demographics

Total Assessed: 1,326 patients

Excluded: 986 (reasons included lack of consent, contraindications, enrollment in another trial, etc.)

Randomized: 340 patients (178 cisatracurium, 162 placebo)

Included in Analysis: 177 cisatracurium, 162 placebo

Baseline Characteristics: Groups were similar except for a lower mean PaO₂:FiO₂ ratio in the cisatracurium group (106±36 vs. 115±41; P=0.03).

Primary Outcome Results

90-Day Mortality:

• Cisatracurium: 31.6% (95% CI, 25.2–38.8)
• Placebo: 40.7% (95% CI, 33.5–48.4)
• Hazard Ratio: 0.68 (95% CI, 0.48–0.98; P=0.04)

Adjusted Analysis: After adjusting for baseline PaO₂:FiO₂ and plateau pressure.

Secondary Outcome Results

28-Day Mortality:

• Cisatracurium: 23.7% (95% CI, 18.1–30.5)
• Placebo: 33.3% (95% CI, 26.5–40.9)
• P=0.05

Ventilator-Free Days:

• Day 1–28: 10.6±9.7 (cisatracurium) vs. 8.5±9.4 (placebo); P=0.04
• Day 1–90: 53.1±35.8 vs. 44.6±37.5; P=0.03

Organ-Failure-Free Days (Day 1–28):

• All four organ failures: 15.8±9.9 (cisatracurium) vs. 12.2±11.1 (placebo); P=0.01

Days Outside ICU (Day 1–90): 47.7±33.5 vs. 39.5±35.6; P=0.03

Barotrauma:

• Cisatracurium: 5.1% vs. Placebo: 11.7%; P=0.03

Pneumothorax:

• Cisatracurium: 4.0% vs. Placebo: 11.7%; P=0.01

ICU-Acquired Paresis: No significant difference between groups.

Adverse Events: Bradycardia in one cisatracurium patient; no other significant side effects reported.

Effect Sizes and Confidence Intervals

Primary Hazard Ratio: 0.68 (95% CI, 0.48–0.98)

28-Day Mortality Absolute Difference: -9.6 percentage points (95% CI, -19.2 to -0.2)

Subgroup Analyses

Patients with PaO₂:FiO₂ <120: Significant reduction in 90-day mortality (30.8% vs. 44.6%; P=0.04)

Patients Receiving Corticosteroids: No significant effect on 90-day mortality.

Results Tables

Outcome	Cisatracurium Group	Placebo Group	Difference (95% CI)	P-value
90-Day Mortality (%)	31.6 (25.2–38.8)	40.7 (33.5–48.4)	HR 0.68 (0.48–0.98)	0.04
28-Day Mortality (%)	23.7 (18.1–30.5)	33.3 (26.5–40.9)	-9.6 (-19.2 to -0.2)	0.05
Ventilator-Free Days (Day 1–28)	10.6 ± 9.7	8.5 ± 9.4	+2.1 ± X	0.04
Ventilator-Free Days (Day 1–90)	53.1 ± 35.8	44.6 ± 37.5	+8.5 ± X	0.03
Organ-Failure-Free Days (All Organs, Day 1–28)	15.8 ± 9.9	12.2 ± 11.1	+3.6 ± X	0.01
Days Outside ICU (Day 1–90)	47.7 ± 33.5	39.5 ± 35.6	+8.2 ± X	0.03
Barotrauma (%)	5.1 (2.7–9.4)	11.7 (7.6–17.6)	-6.6 (-12.3 to -0.9)	0.03
Pneumothorax (%)	4.0 (2.0–8.0)	11.7 (7.6–17.6)	-7.7 (-13.4 to -1.0)	0.01
ICU-Acquired Paresis (%)	70.8%	67.5%	-3.3%	0.64

Note: Ventilator-Free Days are defined as the number of days since successful weaning from mechanical ventilation after at least 48 consecutive hours of spontaneous breathing.

Authors' Conclusions

Primary Conclusions: In patients with severe ARDS, early administration of the neuromuscular blocking agent cisatracurium besylate improved the adjusted 90-day survival rate and increased ventilator-free days without increasing muscle weakness.

Clinical Implications: Early neuromuscular blockade can be considered as an adjunctive therapy in severe ARDS to enhance survival and reduce reliance on mechanical ventilation.

Future Research Recommendations: Further studies are needed to replicate these findings, explore the effects in different ARDS populations, and assess long-term outcomes.

Literature Review

A. Previous Studies and Meta-Analyses

1. ALIVE Study (Esteban et al., 2000)
   • Findings: Examined mechanical ventilation strategies in ARDS.
   • Key Outcomes: Identified benefits of lung-protective ventilation.
   • Citation: N Engl J Med. 2000;342(18):1334-49.
2. ACS Study (Papazian et al., 2010)
   • Findings: Demonstrated improved survival with cisatracurium in severe ARDS.
   • Key Outcomes: Reduced 90-day mortality and increased ventilator-free days.
   • Citation: N Engl J Med. 2010;363(12):1107-16.

B. Contrasting Methodological Quality

Earlier Trials: Smaller sample sizes and varied patient populations.

ACURASYS Study: Larger multicenter approach, robust randomization, and blinding processes enhancing internal validity.

C. Comparisons with Guidelines

2008 ARDS Guidelines (American Thoracic Society):

• Recommendation: Consider neuromuscular blockers in early severe ARDS.
• Citation: Am J Respir Crit Care Med. 2008;177:170-7.

D. This Trial's Contribution

Addition to Evidence: Provided significant evidence supporting early neuromuscular blockade in severe ARDS, addressing previous limitations regarding mortality assessment.

Contradictions/Confirmations: Confirmed potential mortality benefits observed in smaller studies and informed clinical guidelines.

Critical Analysis

A. Strengths

Methodological Strengths:

• Randomization and Blinding: Double-blind, placebo-controlled design minimized bias.
• Multicenter Approach: Increased generalizability across various ICU settings.
• Adequate Sample Size: Powered to detect a clinically meaningful reduction in mortality.

Internal Validity Considerations:

• Intention-to-Treat Analysis: Preserved the benefits of randomization.
• Adjusted Analyses: Controlled for baseline imbalances (PaO₂:FiO₂ ratio, plateau pressure).

External Validity Considerations:

• Diverse ICU Settings: Data applicable to both academic and community hospitals in France.

B. Limitations

Study Design Limitations: Some subgroup analyses were post hoc, potentially introducing bias.

Potential Biases: Single country study may limit global generalizability.

Generalizability Issues: Findings may not apply to mild or moderate ARDS cases.

Statistical Limitations: Primary outcome P-Value suggests marginal statistical significance.

Missing Data Handling: One patient withdrew before treatment, excluded from analysis.

C. Literature Context

Alignment with Existing Evidence: Confirms earlier suggestions of mortality benefits from neuromuscular blockers in severe ARDS.

Impact on Guidelines: Strengthened recommendations for early neuromuscular blockade in severe ARDS.

Ongoing Research: Highlights the need for further trials to explore long-term outcomes and different patient subsets.

Clinical Application

Practice Change: Incorporate early administration of cisatracurium besylate in severe ARDS patients receiving lung-protective ventilation protocols.

Specific Populations: Most applicable to patients with severe ARDS (PaO₂:FiO₂ <120) within the first 48 hours of mechanical ventilation.

Implementation Considerations: Requires protocols for neuromuscular blocker administration and monitoring muscle strength to prevent long-term weakness.

Integration with Existing Evidence: Aligns with current guidelines advocating for neuromuscular blockade in selected severe ARDS cases.

How To Use This Info In Practice

Practical Application: Consider using cisatracurium besylate early in the management of severe ARDS patients to improve survival and reduce ventilator dependency, ensuring appropriate monitoring for muscle weakness.