Context & Rationale

• Background

  Historically, patients with acute lung injury (ALI) or ARDS were often ventilated with tidal volumes of 10–15 mL/kg (actual body weight). Evidence suggested these higher volumes could worsen ventilator-induced lung injury (VILI) by overdistending alveoli.

• Why This Matters

  Investigators hypothesized that using lower tidal volumes (6 mL/kg predicted body weight) and thus lower plateau pressures would reduce iatrogenic lung damage and improve survival in ALI/ARDS.

Design & Methodology

Trial Design

• Design

  Randomised, multicentre, controlled trial conducted across 10 U.S. teaching hospitals (the ARDS Network).

• Factorial Trial

  ARMA was part of a factorial design, including the investigation of ketoconazole (compared with placebo) in the first 234 patients, and lisofylline (compared with placebo) in the last 194 patients.

Population

• Inclusion Criteria

  • Adults with acute lung injury (ALI) or ARDS, defined by PaO₂/FiO₂ ≤300 for ALI and ≤200 for ARDS, onset within 36 hours
  • Bilateral pulmonary infiltrates on chest imaging not primarily due to left atrial hypertension
• Exclusion Criteria

  ARDS duration >36 hours, certain comorbidities, or any condition requiring immediate alternative ventilator strategies

Intervention

• Low Tidal Volume (LTV) Arm
• Tidal Volume

  ~6 mL/kg of predicted body weight

• Plateau Pressure

  ≤30 cm H₂O

• Permissive Hypercapnia

  Mild “permissive hypercapnia” was accepted to maintain these low tidal volumes

Control

• Traditional Tidal Volume (TTV)
• Tidal Volume

  ~12 mL/kg predicted body weight

• Plateau Pressure

  Plateau pressures up to ~50 cm H₂O allowed

Statistical Plan

• Effect Size

  A 9–10% absolute reduction in mortality (e.g., from ~40% to ~30%)

• Sample Size

  Over 750 patients would provide 90% power to detect this effect size at the 5% significance level

• Analysis

  Not stated, but presumed to be intention-to-treat

Other

• Blinding

  Different ventilator settings made blinding impossible; however, protocols were strictly standardized to reduce performance bias.

• Follow Up

  Up to 180 days (6 months) post-randomization for mortality outcomes.

Key Results

• Early Stopping

  The trial was stopped after the fourth interim analysis for efficacy

Primary Outcome - Mortality

• 28 Day Mortality

  • 31.0% vs 39.8%
  • Absolute Difference: 8.8%
  • Relative Risk: ~0.78 (95% CI, 0.65–0.93)
  • p = 0.007

  • (While 180-day mortality was the formal primary endpoint in the study, 28-day mortality is commonly cited. Both favored the LTV arm.)

Secondary Outcomes

• Ventilator-Free Days (28 days)

  • 12 ± 11 days vs 10 ± 10 days
  • p = 0.007
• Organ Failure–Free Days (28 days)

  • 15 ± 12 days vs 12 ± 11 days
  • p = 0.006
• Barotrauma

  • ~11% vs ~14%
  • p ≈ 0.37
• Plateau Pressure (Day 1)

  • 25 ± 6 cm H₂O vs 33 ± 8 cm H₂O
  • p < 0.001
• PaCO₂

  • 44 ± 9 mmHg vs 40 ± 9 mmHg
  • p < 0.001
• pH

  • 7.43 ± 0.07 vs 7.39 ± 0.08
  • p < 0.001

Notes

Internal Validity

• Randomisation & Allocation

  Properly randomised and concealed; baseline characteristics well-balanced

• Performance/Detection Bias

  Unblinded due to obvious ventilator differences, but strict protocols likely minimized bias.

• Protocol Adherence

  Frequent monitoring ensured distinct tidal volumes were maintained. Investigators kept plateau pressures ~25 cm H₂O in LTV vs. ~33 cm H₂O in TTV.

• Outcome Assessment

  Mortality is objective; data collection was robust. Low loss to follow-up.

• Statistical Rigor

  Intention-to-treat analysis used; sample size provided sufficient power. p = 0.007 for mortality strongly suggests a true effect.

• Separation of the Variable of Interest

  • Yes—the two arms had a clear difference;
  • tidal volumes (~6 vs. ~12 mL/kg PBW)
  • plateau pressures (~25 vs. ~33 cm H₂O)
• Key Delivery Aspects

  • Patients were enrolled within 36 hours of ARDS onset (relatively early).
  • The LTV “dose” (6 mL/kg PBW) was well below prior norms and consistently delivered.
  • The control group was arguably a standard practice at the time, but is now recognized as excessively high tidal volumes.

• Conclusion

  The trial had high internal validity

External Validity

• Population Representativeness

  Enrolled diverse adult ICU patients with ALI/ARDS in U.S. teaching hospitals. Subsequent real-world data confirm broad applicability.

• Applicability

  • Confirmed by many follow-up trials in varied international settings.
  • Some caution in late-presenters (>36 hours) or resource-limited centers, yet the principle of lung protection remains robust.

• Conclusion

  The trial had high external generalisation

Strengths & Limitations

Strengths

• Large, multicenter design

  Strong generalizability (in developed ICU settings).

• Protocol

  Clear protocol ensuring distinct tidal volumes and plateau pressures between groups.

• Benefits

  Demonstrated both a mortality benefit and improved secondary outcomes.

Limitations

• High Tidal Volume Control

  12 mL/kg PBW is now deemed harmful, potentially exaggerating the benefit.

• Early Stopping

  Trial was stopped early for benefit, which can inflate effect size.

• Heterogeneous ARDS Population

  Subgroup analyses (mild vs. severe) were limited.

Interpretation / Why This Matters

• Transformational Trial

  This trial transformed ARDS management, showing that limiting tidal volumes and plateau pressures improves survival.

• Paradigm Shift

  It sparked a paradigm shift, identifying “ventilator-induced lung injury” as a key modifiable factor.

• Landmark Trial

  ARMA became cornerstone evidence for adopting “lung-protective ventilation” in ARDS.

Controversies & Subsequent Evidence

• Control Arm Criticism

  Some argue it was not true “standard care” but rather a harmful practice at 12 mL/kg. Nevertheless, meta-analyses confirm the benefit of ~6 mL/kg.

• PEEP Strategies

  Later ARDSNet trials (e.g., ALVEOLI) assessed higher vs. lower PEEP, but the low tidal volume principle remained a foundation.

• Long-Term Validation

  Multiple external RCTs and observational data consistently replicate improved outcomes with low tidal volumes.

Summary

• Mortality Reduction

  LTV arm had a nearly 9% absolute reduction in mortality.

• Reduced Ventilator-Induced Injury

  Confirmed that alveolar overdistension drives worsening lung injury.

• Control Arm Question

  12 mL/kg PBW is now recognized as excessive.

• Lasting Impact

  Sets the global standard of 6 mL/kg PBW for ARDS ventilation.

Conclusion

• Landmark Trial

  ARMA changed ventilatory practice worldwide and has formed the basis of protective ventilatory practice for a quarter of a century.

Further Reading

Other Trials

• Non-ARDS

  Writing Group for the PReVENT Investigators. Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS. A Randomized Clinical Trial. JAMA 2018;epublished October 24th

• Intraoperative

  Futier. A Trial of Intraoperative Low-Tidal-Volume Ventilation in Abdominal Surgery (IMPROVE study). N Engl J Med 2013; 369:428-437

• ARDS

  Brochard. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trial Group on Tidal Volume Reduction in ARDS. Am J Respir Crit Care Med 1998; 158:1831-1838

• ARDS

  Amato. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347-354.

• ARDS

  Stewart. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 1998;338:355-361.

Systematic Review & Meta Analysis

• Hypercapnoea

  Gendreau. The role of acute hypercapnia on mortality and short-term physiology in patients mechanically ventilated for ARDS: a systematic review and meta-analysis. Intensive Care Med 2022;48(5):517-534

Observational Studies

• Global Epidemiology

  Bellani. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA 2016;315(8):788-800

Guidelines

• American

  An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2024;209(1):24–36

• American

  American Association for the Surgery of Trauma/American College of Surgeons Committee on Trauma Clinical Protocol for Management of Acute Respiratory Distress Syndrome and Severe Hypoxemia. J Trauma Acute Care Surg 2023;epublished June 12th

• European

  Grasselli. ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies. Intensive Care Med 2023;epublished June 16th

• Japanese

  Tasaka. (Japanese) ARDS Clinical Practice Guideline 2021. J Intensive Care 2022;10:32