Landmark Trials: ARDSnet
The Article: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. N Engl J Med. 2000 May 4;342(18):1301-8. (PMID: 10793162)
The Idea: ALI and ARDS carry a very high mortality (40-50%). Prior to this landmark study these patients were classically intubated and mechanically ventilated with tidal volumes of 10-15 cc/kg. However animal studies prior to publication of this study had demonstrated that high volume ventilation can induce further lung injury and release of inflammatory mediators can induce injury to other organs. Uncontrolled studies comparing high vs low tidal volume ventilation ARDS/ALI patients had resulted in mixed conclusions. The authors of this study hypothesized that use of lower tidal volume mechanical ventilation will improve clinically important outcomes in ALI/ARDS patients.
Design: Un-blinded multicenter (10 academic) randomized control trial
Patient population: Adult patients with ARDS / ALI (defined as PO2:FiO2 < 300, bilateral pulmonary infiltrates on CXR, absence of left atrial hypertension). Exclusion criteria included (but not limited to): <18 yo, pregnant patients, obese patients, increased ICP, burns > 30% TBSA
Randomization: 861 patients were randomized to either the traditional tidal volume parameters (12 cc/kg predicted body weight, plateau pressures 45-50 cm H2O) or lower tidal volume parameters (6 cc/kg PBW, plateau pressures 25-30 cm H2O).
Primary outcomes: Death before discharge, ventilator free days
Secondary outcomes: Days without organ or system failure (defined as SBP < 90, need for vasopressors, PLT < 80K, etc), days without barotrauma (ptx, pneumomediastinum, pneumatocele); IL-6 (inflammatory mediator) was measured on day 0 and day 3
Interim analysis was conducted after enrollment of every ~200 patients.
The Results: The trial was stopped at the fourth interim analysis as lower tidal volume ventilation of ARDS/ALI patient was determined to have a profound mortality benefit in ARDS/ALI patients (mortality rate traditional tidal volume – 39.8%, mortality rate lower tidal volume – 31%; p = .007; ARR = 8.8%, NNT = 11.4). The lower tidal volume cohort also had significant greater ventilator free days, and significantly fewer median number of days without organ failure. Surprisingly there was no statistically significant difference in the incidence of barotrauma between the two groups. Finally, the authors noted two important trends: the lower tidal volume cohort required more PEEP and FiO2 on days 1 and 3, however by day 7 had lower oxygenation requirements than the traditional tidal volume cohort. Additionally, the difference of IL-6 concentrations between day 0 and day 3 was greater in the lower tidal volume cohort. These trends suggest higher PEEP may have beneficial to the ARDS/ALI patients, and lower tidal volume correlate with a decrease in inflammatory mediators. Author’s Conclusion: “High priority should be given to preventing excessive lung stretch during adjustments to mechanical ventilation, and this lower VT protocol should be used in patients with ALI and ARDS”
The Takeaway: This is a landmark, high quality randomized controlled trial with a focus on patient centered outcomes that led to a paradigm shift in the mechanical ventilation strategy of patients with ALI and ARDS. However this article does not have a specific Emergency Department focus, and was specific to patients with pre-existing ARDS/ALI. The ARDSnet trial has since spawned a panoply of research applying the same low tidal volume lung protective ventilation strategies to other patient populations – such as those presenting to the emergency department without pre-existing ARDS/ALI. A 2012 meta-analysis (Schultz et al, 2012; PMID: 23093163) of both randomized and observational studies concluded that lower tidal volume ventilation was associated with clinical benefit (ventilator associated lung injury, and mortality) in patients without pre-existing ARDS/ALI. However, despite this knowledge observational studies have demonstrated that potentially injurious and variable ventilation practices are still commonplace in ED’s where mechanical ventilation is frequently initiated (Kollef et al, 2015; PMID: 25742126). The 2017 LOV-ED Trial demonstrated that implementation of a standardized lung protective ventilation protocol in the ED is not only feasible, but is associated with reduction in pulmonary complications, hospital mortality, and healthcare resource use.