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Brower RG, et al. "Ventilation With Lower Tidal Volumes As Compared With Traditional Tidal Volumes For Acute Lung Injury And The Acute Respiratory Distress Syndrome". The New England Journal of Medicine. 2000. 342(18):1301-1308.
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Clinical Question

In patients with ALI/ARDS receiving mechanical ventilation, how does a lung protective strategy using lower tidal volumes compare with traditional ventilation protocols in decreasing mortality and ventilator-free days?

Bottom Line

In patients with ARDS, low tidal volume ventilation (initial TV 6ml/kg PBW) had lower mortality and more ventilator-free days.

Major Points

ARDS is mediated by alveolar damage from the release of inflammatory mediators. Traditional approaches to mechanical ventilation used tidal volumes of 10-15ml/kg PBW. However, multiple animal studies and observational studies showed that these large tidal volumes and the consequential elevated plateau pressures were associated with significant barotrauma.

The 2000 Acute Respiratory Distress Syndrome Network (ARDSNet) trial — sometimes referred to as the ARMA trial — was conducted to compare a lung-protective strategy using lower tidal volumes of 6ml/kg of PBW (goal plateau pressure 25-30mmHg) with conventional mechanical ventilation using tidal volumes of 12ml/kg of PBW (goal plateau pressure 45-50 mmHg). The mean tidal volumes on days 1 to 3 were 6.2 vs. 11.8 ml/kg PBW and the mean plateau pressures were 25 vs. 33 cm H2O, respectively. The trial was stopped prematurely when the low tidal volumes arm demonstrated a significant decrease in mortality (31% vs. 40%) and more ventilator-free days (12 vs. 10 days) compared to the traditional tidal volumes arm. The absolute risk reduction of 9% correlates with a number needed to treat of 11 patients in order to prevent one death.

This trial was investigated by the Office of Human Research Protections (OHRP) for ethical concerns, specifically that the educational materials as part of the informed consent process were inadequate. Additionally, the use of 12 mL/kg of PBW has been criticized by some as higher than the standard of care.[1]

Despite the trial's controversies, the benefit of low Vt ventilation has been supported by a recent Cochrane meta-analysis.[2] The ARDSNet protocol's low tidal volume in ARDS[3] has become the standard of care.[4]


Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[5]

  • Recommend targeting tidal volumes of 6 mL/kg of predicted body weight in ARDS from sepsis (strong recommendation, high quality of evidence)


  • Multicenter, parallel-group, randomized controlled trial
  • N=861
    • Low tidal volumes: starting at 6ml/kg PBW and plateau pressure ≤30cmH2O (n=432)
    • Traditional tidal volumes: starting at 12ml/kg PBW and plateau pressure of ≤50cmH2O (n=429)
  • Setting: 10 university-affiliated ARDSNet centers
  • Enrollment: March 1996 to March 1999 (terminated early after the fourth interim analysis)
  • Follow-up: 180 days or until home breathing independently


Inclusion Criteria

  • Age ≥18 years
  • Receiving mechanical ventilation
  • Diagnosis of ALI/ARDS ≤36h prior to enrollment; defined as:
    • Acute decrease in PaO2/FiO2 ratio to ≤300
    • Bilateral pulmonary infiltrates on CXR consistent with presence of edema
    • PCWP of ≤18mmHg without evidence of left atrial hypertension

Exclusion Criteria

  • Participation in other trials within 30 days
  • Pregnancy
  • Increased intracranial pressure, neuromuscular disease that could impair spontaneous breathing, sickle cell disease, or severe chronic respiratory disease
  • Weight more than 1kg/cm of height
  • Burns more than 30% of BSA
  • Estimated 6-month mortality rate >50%
  • History of bone marrow or lung transplantation
  • Child-Pugh class C liver disease

Baseline Characteristics

  • Mean age: 51.5 years
  • Female: 40.5%
  • White: 73%
  • Black: 17.5%
  • Hispanic: 6%
  • APACHE III score: 82.5
  • Mean PaO2:FiO2: 136
  • Mean tidal volume: 670 mL
  • Mean minute ventilation: 13.4 vs. 12.7 L/min (P=0.01)


Patients randomly assigned to receive mechanical ventilation (volume-assist-control mode) with following strategies for tidal volume:

Lower tidal volumes[3] starting at 6 ml/kg PBW, reduced stepwise by 1 ml/kg PBW to maintain plateau pressure ≤30 cmH2O

  • If plateau pressure <25 cmH2O, tidal volume increased stepwise by 1 ml/kg PBW until plateau pressure ≥25 cmH2O or tidal volume 6 ml/kg PBW
  • For severely dyspneic patients, tidal volume could be increased to 8 ml/kg PBW to maintain plateau pressure ≤30 cmH2O
  • Minimal tidal volume: 4 ml/kg PBW; minimal arterial pH: 7.15

Traditional tidal volumes starting at 12 ml/kg PBW, reduced stepwise by 1 ml/kg PBW to maintain plateau pressure ≤50 cmH2O

  • If plateau pressure <45 cm H2O, tidal volume increased stepwise by 1 ml/kg PBW until plateau pressure ≥45 cmH2O or tidal volume 12 ml/kg PBW
  • Minimal tidal volume: 4 ml/kg PBW; minimal arterial pH: 7.15

Patients monitored until day 28 or death for signs of system failure:

  • Circulatory failure: SBP ≤90mmHg or need for vasopressor
  • Coagulation failure: platelets ≤80,000 mm3
  • Hepatic failure: serum bilirubin ≥2mg/dL
  • Renal failure: serum creatinine ≥2mg/dL


Comparisons are lower tidal volumes vs. traditional tidal volumes.

Primary Outcomes

180-day mortality
31.0% vs. 39.8% (RR 0.78; P=0.007)
Ventilator-free days, days 1-28
12 vs. 10 (P=0.007)
Breathing without assistance by day 28
65.7% vs. 55.0% (P<0.001; NNT 9)

Secondary Outcomes

Days without non-pulmonary organ or system failure, days 1 to 28
15 vs. 12 (P=0.006)
Days without circulatory failure
19 vs. 17 (P=0.004)
Days without coagulation failure
21 vs. 19 (P=0.004)
Days without renal failure
20 vs. 18 (P=0.005)
Barotrauma (new pneumothorax, pneumomediastinum, subcutaneous emphysema, pneumatocele)
10% vs. 11% (P=0.43)
Mean tidal volumes (ml/kg of PBW)
6.2 vs. 11.8 (P<0.001)
Mean plateau pressures (cm H2O)
25 vs. 33 (P<0.001)
Peak inspiratory pressures (cm H2O)
32 vs. 39 (P<0.05)


  • The trial studied more than just low Vt ventilation; a standardized PEEP protocol was used as well.[6]
  • The mortality benefit may be from improved oxygen delivery to tissues rather than progression of lung disease.[6]
  • The mortality benefit in the low Vt group may have been because the traditional Vt group had unnecessarily high Vt.[6]
  • The traditional Vt group may not have been subjected to the best known therapy — an intermediate tidal volume (10 mL/kg of PBW) therapy was utilized at multiple centers at the time. The investigators may have, therefore, submitted the participants to unnecessary harm.[1]
  • The informed consent educational materials was deemed to have "failed to describe adequately the reasonably foreseeable risks and discomforts" by the OHRP.[1]


Supported by the National Heart, Lung, and Blood Institute.

Further Reading

  1. 1.0 1.1 1.2 Steinbrook R. "Health policy report: How best to ventilate? Trial design and patient safety in studies of the acute respiratory distress syndrome." The New England Journal of Medicine. 2003;348:1393-1401.
  2. Petrucci N and De Feo C. "Lung protective ventilation strategy for the acute respiratory distress syndrome." The Cochrane Library. Published online 2013-02-28. Accessed 2013-07-18.
  3. 3.0 3.1 PDF File - PDF ARDSNet protocol ventilator settings reference card
  4. Cite error: Invalid <ref> tag; no text was provided for refs named ssc
  5. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  6. 6.0 6.1 6.2 Multiple authors. "Correspondence: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury." The New England Journal of Medicine. 2000;343:812-814.