ATS Reading List


Diagnosis, risk factors, and long-term outcomes

ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012; 307:2526-33. The new definition will likely establish a new standard for the clinical diagnosis of ARDS for future clinical trials. Also noteworthy is elimination of the term "acute lung injury" from the clinical definition.
PMID: 22797452

Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for development of ARDS. Am J Respir Crit Care Med 1995;151:293-301. This study describes the incidence of ARDS in patients with various clinical risk factors. Also found 1) greater mortality in at-risk patients that develop ARDS and 2) ARDS develops within 48 to 72 hours of the time clinical risk is identified in the vast majority of patients.
PMID: 7842182

Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011 Apr 7;364(14):1293-304. This study provides the longest and most comprehensive follow-up of ARDS survivors to date, emphasizing the importance of long-term neuromuscular and psychiatric dysfunction despite nearly complete recovery of lung function
PMID: 21470008
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Treatment: Ventilator Strategies

Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967;2:319-23. Original description of ARDS and use of PEEP in treating ARDS.
PMID: 4143721

ARDS Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for ALI and ARDS. N Engl J Med. 2000;342:1301-8. Results of the landmark ARMA study found the use of low (6 ml/kg predicted weight) rather than "standard" (12 ml/kg predicted weight) tidal volumes reduced mortality from 40 to 30%. These results provide much of the basis for use of low- stretch/low tidal volume ventilation strategy in acute lung injury.
PMID: 10793162
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Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in ARDS. N Engl J Med. 1998;338:347-54. Small, randomized, study famous for using a combination of the lower inflection point of the pressure-volume curve to set PEEP, recruitment maneuvers (CPAP 35-40 cm x 40 sec.), and low-tidal volumes (< 6cc/kg). 28-day mortality was lower in the intervention group, but the conventional group had an unusually high mortality (71%). Patients overall received higher PEEP than in the ARMA study.
PMID: 9449727
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Comparisons of High vs. Low PEEP

Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-36. A NHLBI ARDS net randomized trial comparing high and low PEEP strategies in 549 patients with ALI or ARDS found no significant difference in mortality, ventilator-free days, ICU-free days, or organ failure-free days in the two groups.
PMID: 15269312
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Meade MO, Cook DJ, Guyatt GH, et al. Lung open ventilation study investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008; 299:637-45. This study also found no significant difference in 28-day mortality with higher PEEP (28.4 vs 32.3%, p = 0.2) despite lower rates of refractory hypoxemia (4.6 vs. 10.2%, p = 0.01) and reduced pre-defined need for rescue therapies (5.1 vs. 9.3%, p = 0.045). Of note, the target plateau pressure was higher than in other high vs. low PEEP studies (</equal to 40 cm H2O).
PMID: 18270352
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Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:646-55. The ExPress study compared low vs. high PEEP in 767 patients with ARDS receiving low tidal volume ventilation. In the high-PEEP group, PEEP was adjusted to a target plateau pressure of 28 to 30 cm H2O regardless of oxygenation while target PEEP in the minimal distension group was 5 to 9 cm H2O. Mortality at 28 days did not differ, but the high-PEEP group had a higher median number of ventilator-free days and required fewer "rescue" interventions such as proning. It appears the greatest benefit to a high-PEEP strategy is in patients with more severe lung edema, but whether there is a survival benefit in this subpopulation is still unclear. See also results of the Lung Open Ventilation Study (LOVS) in the same issue (Stewart TE et al.).
PMID: 18270353
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Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:347-55. In this study the authors hypothesized that "driving pressure" (Pplat - PEEP) would better predict outcomes rather than Vt or PEEP values. They derived, refined, and then validated their model using 9 older studies and a strategy called multilevel mediation analysis. They found that driving pressure was the variable most highly associated with survival. Although provocative, the study authors and editorialists caution that these findings should be used to design future ARDS trials, but not to guide care at the bedside.
PMID: 25693014
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Neuromuscular Blockade

Papazian L, Forel JM, Gacouin A, et al. for the ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-16. This multicenter RCT of 340 patients with severe ARDS found early use of 48 hours of neuromuscular blockade reduced mortality compared to placebo (NNT of 11 to prevent one death at 90 days in all patients, and a NNT of 7 in a prespecified analysis of patients with a PaO2:FiO2 less than 120). Of note, patients randomized to paralytic did not have an increased incidence of ICU-acquired weakness at 28 days.
PMID: 20843245
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Prone Positioning

Taccone P, Pesenti A, Latini R, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome. JAMA. 2009;302:1977-1984. Prior studies on prone positioning were limited by short duration of pronation. The Prone-Supine II Study randomized 342 adults at 25 centers to prone position 20 hours per day for the duration of ARDS, or 24 hour supine position. No significant change in ICU or 28 day mortality was identified. However, the prone position group experienced a statistically significant increased incidence of adverse events including need for additional sedation, airway obstruction, transient hypoxia, hypotension/arrhythmia, and loss of venous access. These results were in contrast to post hoc and meta-analyses of earlier trials.
PMID: 1990318
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Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013; 368:2159-2168. In contrast to previous studies of prone positioning, this group found significantly decreased (and strikingly low) mortality at 28 (32.8 vs.16%) and 90 (41% vs. 23.8%) days without an increase in adverse events among 466 patients with severe ARDS (PaO2/FIO2 < 150 mmHg). The treatment group was placed in the prone position within the first 3-4 days. Normal ICU beds were used.
PMID: 23688302
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Alternative Modes

High Frequency Oscillation: The following trials found no mortality benefit from HFOV being applied early in moderate and severe ARDS. OSCILLATE found an increased mortality rate in the treatment group. This was in the setting of a higher average mean airway pressure and increased vasopressor use. These findings were in contrast to the results of a meta-analysis suggesting mortality benefit. It should be noted that this was not a study of HFOV as a salvage maneuver, but as a primary mode in ARDS.

Young D, Lamb SE, Shah S, et al. High-Frequency Oscillation for Acute Respiratory Distress Syndrome. N Engl J Med. 2013;368:806-13. OSCAR.
PMID: 23339638
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Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013;368:795-805. OSCILLATE.
PMID: 23339639
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Fessler HE, Derdak S, Ferguson ND, et al. A protocol for high-frequency oscillatory ventilation in adults: Results from a roundtable discussion. Crit Care Med 2007;35:1649-54. This consensus statement was composed by a panel of prominent HFOV researchers and clinicians, and provides guidelines for the use and management of HFOV.
PMID: 17522576

Modrykamien A, Chatburn RL, RW Ashton. Airway pressure release ventilation: an alternative mode of mechanical ventilation in acute respiratory distress syndrome. Cleve Clin J Med. 2011 Feb;78(2):101-10. A concise description of APRV as well as discussion of the physiologic principles behind "open lung" ventilation.
PMID: 21285342
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Rescue Therapies

Nitric Oxide

Afshari A, Brok J, Møller AM, et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev 2010 7;(7):CD002787. Following on the heels of a systematic review out of Toronto in 2007, this analysis again demonstrates the lack of clinical benefit with inhaled nitric oxide in ARDS and acute lung injury, with an increased risk of acute kidney injury.
PMID: 20614430
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Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009; 374:1351-63. Highlighting both regionalization of care and use of ECMO, this trial showed that transfer to an ECMO-ready facility (75% of those transferred actually received ECMO) led to an NNT of 6 to prevent one death or severe disability at six months compared to standard care. The study was limited by the lack of a mandated lung-protective strategy in the control group; 93% of those transferred for possible ECMO received a lung-protective strategy, compared to 70% in the control group.
PMID: 19762075
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Treatment: Corticosteroids

Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354:1671-84. This study randomized 180 patients with persistent ARDS (7 to 28 days after onset) to methylprednisolone (daily dose 2 mg/kg x 14 days then 1 mg/kg x 7 days) vs. placebo. Hospital mortality and 180-day survival were comparable, but patients enrolled 14 or more days after ARDS onset had increased 60-day mortality (35% vs. 8% placebo, p = .02).
PMID: 16625008
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Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007; 131:954-63. This study of 91 patients with severe ARDS added fuel to the debate over systemic corticosteroid use in ARDS. The intervention group received steroids within 72 hours of ARDS diagnosis and a slow taper. Steroid recipients had decreased duration of mechanical ventilation and ICU stay. The higher proportion of patients with catecholamine-dependent shock among controls, cross over from control to steroids in "nonresponders" at day 7, and 2:1 randomization of treatment to control are among the concerns raised since its publication.
PMID: 17426195
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Treatment: Fluid management

Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006; 354:2564-75. FACTT Trial. This randomized study compared conservative fluid management using a complex protocol to a liberal fluid approach over seven days in 1000 patients with acute lung injury. Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management shortened the duration of mechanical ventilation and ICU stay without increasing nonpulmonary-organ failure.
PMID: 16714767
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***See also Mechanical Ventilation

Last Reviewed: June 2017