Diagnosis, long-term outcomes, and pathophysiology:

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

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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The following two articles provide an in-depth review of gas exchange and lung mechanics in ARDS.
Radermacher P, Maggiore SM, Mercat A. Fifty years of research in ARDS. Gas exchange in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017; 196:964-984.
PMID: 28406724

Henderson WR, Chen L, Amato MBP, et al. Fifty years of research in ARDS. Respiratory mechanics in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017; 196:822-833.
PMID: 28306327

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 MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747-55. This retrospective analysis of previous ARDS trials found driving pressure was the ventilator variable most strongly associated with survival and that changes in ventilator settings resulting in reduction in driving pressure were associated with increased survival. 
PMID: 25693014
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Comparisons of High vs. Low PEEP:

The following 4 trials investigated the use of high vs. low PEEP in ARDS. All found no difference in mortality while Meade et al and Mercat et al found less need for rescue therapies.  On the whole, these studies pointed toward the greatest benefit of high PEEP among patients with severe ARDS. 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.
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.
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.
PMID: 18270353
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Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura EA, Laranjeira LN, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017; 318:1335-45. Multicenter trial of 1010 patients with moderate to severe ARDS randomized to low PEEP or a lung recruitment maneuver and PEEP titrated to the best respiratory-system static compliance (intervention). The intervention group had increased mortality at 28 days (55% vs 49%; p=0.041), and increased risk of pneumothorax. ART is the first major study of the “open lung approach” to show harm.  Concerns raised about the study include the relatively high mortality in both groups as well as the method of recruitment.
PMID: 28973363
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Oxygenation Goals:

Barrot L, Asfar P, Mauny F, et al. LOCO2 Investigators and REVA Research Network. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020; 382:999-1008. This LOCO2 trial compared oxygenation targets of PaO2 55-70 mmHg vs. 90-105 mmHg, or their equivalent saturations, Enrollment was stopped for futility after 205 subjects. There was no difference in 28-day mortality (primary outcome) and 5 episodes of mesenteric ischemia in the O2 conservative group.
PMID: 32160661

***See also Ventilation and Weaning for oxygen goals in non-ARDS patients

Prone Positioning:

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.
PMID: 23688302
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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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Combes A, Hajage D, Capellier G et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. 2018; 378:1965-1975. The multicenter EOLIA randomized 249 patients with very severe ARDS to immediate VV ECMO vs standard care. 60-day mortality was lower in the ECMO group but the difference was not statistically significant (35% vs. 46%, p value 0.09). The study was stopped early for futility despite a trend toward benefit. Of note, 28% of control patients crossed over to ECMO due to refractory hypoxemia, with 43% of this group surviving.
PMID: 29791822
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***For additional information, see ECMO section for general reviews on use of VV and VA circuits.

Neuromuscular Blockade:

Moss M, Huang DT, Brower RG, et al. Early neuromuscular blockade in acute respiratory distress syndrome (ROSE). N Engl J Med. 2019;380:1997-2008. This RCT of 1006 patients with moderate to severe ARDS found no difference in 90 day mortality with early use of a 48 hour infusion of neuromuscular blockade compared to usual care. This trial was similar to the ACURASYS trial except for the use of lighter sedation targets in the usual care group. There was no difference in rates of ICU-acquired weakness or recall of paralysis. Trial was stopped early for futility.
PMID: 31112383
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Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363:1107-16. Unlike the subsequent ROSE study, this RCT of 340 patients with severe ARDS found the use of neuromuscular blockade initiated within 48 hours of admission and continued for 48 hours reduced mortality.
PMID: 20843245
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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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Villar J, Ferrando C, Martínez D, et al.Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020; 8:267-276. This trial randomized 277 ARDS patients with PaO2/FIO2 < 200 despite PEEP ≥ 10 and FIO2 ≥ 0.5 to 10 days of dexamethasone or routine care. Mean ventilator-free days was 4.8 days higher (95% CI 2.57 to 7.03) in the dexamethasone group and 60 day mortality was lower in the dexamethasone group (21% vs 36% with 95% CI -25.9 to – 4.9). Slow rate of patient recruitment and lack of blinding are limitations.
PMID: 32043986

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 is widely cited as the rationale for aggressive diuresis in ARDS patients. Of note, the study protocol is highly complex and relies on CVP and PA catheter measurements, limiting its direct clinical applicability.
PMID: 16714767
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***See also Ventilation and Weaning