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

E-cigarette/Vaping Associated Lung Injury

Chatham-Stephens K, Roguski K, Jang Y, et al. Characteristics of hospitalized and nonhospitalized patients in a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury - United States, November 2019. MMWR Morb Mortal Wkly Rep. 2019; 68:1076-1080. Report on symptoms, demographic data, and management of patients with EVALI during 2019 outbreak.

PMID: 31751326

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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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Comparisons of High vs. Low PEEP

The following three 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; 318:1335-1345. Multicenter trial of 1010 patients with moderate to severe ARDS randomized to low PEEP (control) or a lung recruitment maneuver and PEEP titration according 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 requiring draining (3.2% vs 1.2%; p=0.03). ART is noteworthy for being 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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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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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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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. Normal ICU beds were used.

PMID: 23688302

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Alternative Modes

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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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

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 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 Mechanical Ventilation