Acute Respiratory Distress Syndrome (ARDS)

Definition, Etiology, PathogenesisTop

1. According to the 2012 Berlin definition, acute respiratory distress syndrome (ARDS) is characterized by the following:

1) Acuity of onset or new or worsening respiratory symptoms within 1 week of a known clinical insult.

2) Chest imaging abnormalities: Bilateral opacities on plain radiographs or computed tomography (CT) scans not fully explained by effusions, lobar or lung collapse, or nodules.

3) Origin of pulmonary edema: Respiratory failure not fully explained by congestive heart failure or fluid overload. Patients with no risk factors for ARDS (see below) may require objective assessment (eg, echocardiography) to exclude hydrostatic edema.

4) Hypoxemia, as assessed in a ventilated patient by a ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) (in a healthy person breathing atmospheric air: PaO2 = 97 mm Hg; FiO2 = 0.21; PaO2/FiO2 = 470 mm Hg; at altitudes >1000 meters above the sea level use the formula: PaO2/FiO2 × atmospheric pressure in mm Hg/760). Based on this, ARDS is classified as one of the following:

a) Mild ARDS: 200 mm Hg <PaO2/FiO2 ≤300 mm Hg with positive end-expiratory pressure (PEEP) or noninvasive continuous positive airway pressure (CPAP) ≥5 cm H2O.

b) Moderate ARDS: 100 mm Hg <PaO2/FiO2 ≤200 mm Hg with PEEP ≥5 cm H2O.

c) Severe ARDS: PaO2/FiO2 ≤100 mm Hg with PEEP ≥5 cm H2O.

2. Causes (risk factors) of ARDS:

1) Direct lung injury: A direct insult to the lungs as a result of pneumonia (including viral causes), aspiration of gastric contents, pulmonary contusion, inhalation injury, near drowning.

2) Indirect lung injury: An indirect insult to the lungs as a result of sepsis, shock, acute pancreatitis, major burn injury, drug overdose, transfusion-related acute lung injury (TRALI), prolonged cardiopulmonary bypass. This list is incomplete and it is important to note that pneumonia, aspiration of gastric contents, and sepsis account for >85% of ARDS cases.

3. Pathogenesis of ARDS: An uncontrolled inflammatory process causing damage to the alveolar-capillary membrane with transfer of protein-rich fluid and cells from the vessels to the alveoli, destruction and impaired production of surfactant, collapse and edema of the alveoli (exudative phase); destruction of the alveolar septa by inflammatory cell infiltration, impaired gas exchange, reduced lung compliance, and eventually respiratory failure (with dominant hypoxemia) and (acute) pulmonary hypertension. Reparative processes begin within 2 to 3 weeks (proliferative phase) and regeneration of damaged cells or production of collagen by fibroblasts is possible at later stages (fibrotic phase).

DiagnosisTop

See Acute Respiratory Failure.

Diagnostic Criteria

See Definition, Etiology, Pathogenesis, above.

TreatmentTop

See Acute Respiratory Failure.

The initial treatment of patients with ARDS is the same as for other causes of acute respiratory failure. Two elements fundamental to the management of ARDS are treatment of the underlying disorder and supportive care, the mainstay of which is mechanical ventilation. Noninvasive ventilation or high-flow oxygen therapy may be considered in mild ARDS; with worsening severity, invasive ventilation is more appropriate.

Invasive Mechanical Ventilation

Ventilatory management for ARDS focuses on preventing ventilator-induced lung injury with lung-protective ventilation and conservative fluid therapy to prevent excess lung water formation.

A lung-protective ventilation strategy that targets tidal volumes in the range of 4 to 8 mL/kg of predicted body weight is associated with higher survival rates than traditional tidal volumes in the range of 10 to 12 mL/kg.Evidence 1 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to some inconsistency across trials for a critical outcome, mortality. However, the finding of reduced mortality was statistically significant. Burns KE, Adhikari NK, Slutsky AS, et al. Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis. PLoS One. 2011 Jan 28;6(1):e14623. doi: 10.1371/journal.pone.0014623. Review. PubMed PMID: 21298026; PubMed Central PMCID: PMC3030554.

There is a mobile educational application available for health-care professionals in charge of patients on mechanical ventilation (www.opencriticalcare.org).

Deceasing ventilator driving pressure may also prevent ventilator-induced lung injury. Driving pressure can be calculated as plateau pressure minus PEEP. Plateau pressure is measured as the pressure applied to small airways and alveoli during an inspiratory pause on the mechanical ventilator. During the inspiratory pause, gas flow (and therefore resistance) is zero; thus, the plateau pressure reflects respiratory system compliance for the tidal volume delivered. With progression of ARDS, maintaining stable (even low) tidal volume when confronted with decreasing compliance requires increases in driving pressure. Consequently, increased mechanical stress is applied to the still available functional lung. It is recommended that tidal volume be decreased in order to maintain a stable driving pressure. This single variable is more strongly associated with survival than low tidal volume ventilation or higher PEEP.Evidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015 Feb 19;372(8):747-55. doi: 10.1056/NEJMsa1410639. PubMed PMID: 25693014.

The relative benefit of a high PEEP versus a low PEEP strategy is not altogether clear; a higher PEEP strategy does not appear to be harmful and may improve survival in patients with moderate to severe ARDSEvidence 3 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence from this individual patient data meta-analysis lowered due to the fact that high-PEEP treatment strategies varied in the studies of the review, the direction of survival effect was not consistent across the 3 major trials (one suggested possible harm), and the statistically significant finding was limited to a subgroup analysis (which met all criteria for credibility). Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010 Mar 3;303(9):865-73. doi: 10.1001/jama.2010.218. Review. PubMed PMID: 20197533. (Table 1).

Esophageal pressure monitoring has long been considered for identifying an ideal PEEP strategy; however, titrating PEEP according to the esophageal pressure has yet to provide a clear benefit.Evidence 4Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Beitler JR, Sarge T, Banner-Goodspeed VM, et al; EPVent-2 Study Group. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019 Mar 5;321(9):846-857. doi: 10.1001/jama.2019.0555. PubMed PMID: 30776290; PubMed Central PMCID: PMC6439595. Prone ventilation improves ventilation-perfusion matching and keeps alveolar units open. It may reduce mortality in severe ARDS compared with conventional ventilation using relatively low PEEP.Evidence 5High Quality of Evidence (high confidence that we know true effects of the intervention). Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20. PubMed PMID: 23688302. This strategy has not been tested against ventilation using higher PEEP strategies. Center-expertise in proning is another important consideration to avoid adverse complications, such as tube dislodgement or pressure ulceration. In our setting, in patients who will likely tolerate proning and in whom other treatments (PEEP, protected mode) have been optimized but the PaO2/FiO2 ratio remains <150 to 200 mm Hg, we use prone ventilation. The likelihood of benefit increases with the severity of hypoxia, relatively early application, and with duration of daily proning (likely >16 hours).Evidence 6Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Bloomfield R, Noble DW, Sudlow A. Prone position for acute respiratory failure in adults. Cochrane Database Syst Rev. 2015 Nov 13;(11):CD008095. doi: 10.1002/14651858.CD008095.pub2. Review. PubMed PMID: 26561745; PubMed Central PMCID: PMC6464920.

The use of extracorporeal membrane oxygenation (ECMO) requires consideration of not only overall incomplete evidence of its efficacy but also considerations of local expertise, resource use, and implication of transfer. In our setting, we consider the use of ECMO (and transfer) in patients with very severe refractory hypoxia, potentially reversible acute respiratory failure, and otherwise having a realistic chance for functional recovery.

Other Treatment Strategies

1. Volume status: Although it is important to distinguish ARDS from volume overload or heart failure, these entities may coexist in a significant number of patients. Consequently, a conservative fluid management strategy may improve lung function and shorten the duration of mechanical ventilation without compromising non-pulmonary organ function.Evidence 7Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and imprecision.Silversides JA, Major E, Ferguson AJ, et al. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155-170. doi: 10.1007/s00134-016-4573-3. Epub 2016 Oct 12. Review. PubMed PMID: 27734109. This may be best accomplished by avoiding fluid administration after reversal of shock.

2. Neuromuscular blockade: Although continuous neuromuscular blockade for severe ARDS has been common practice (the ACURASYS trial), early routine administration of such treatment in addition to a high PEEP strategy has not improved mortality in the most recent and largest trial and probably should be used more selectively.Evidence 8Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, Brower RG, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. Epub 2019 May 19. PubMed PMID: 31112383; PubMed Central PMCID: PMC6741345.

3. Glucocorticoids: Data on the use of glucocorticoids are imprecise and obtained in different populations; however, early (within 7 days) use of smaller doses of methylprednisolone (1 mg/kg) or higher doses (2 mg /kg) when started between 7 and 14 days is suggested.Evidence 9alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and the risk of bias.Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2017 Dec;43(12):1751-1763. doi: 10.1007/s00134-017-4919-5. Epub 2017 Sep 21. Erratum in: Intensive Care Med. 2018 Feb 23;:. PubMed PMID: 28940011. Glucocorticoids should not be stopped abruptly but slowly tapered down over the course of 6 to 14 days. The use of glucocorticoids in hypoxic respiratory failure associated with coronavirus disease 2019 (COVID-19), with or without ARDS, is one of the mainstays of the therapy.

Rescue Therapies

In the most severe cases of ARDS with hypoxemia and/or hypercapnia refractory to mechanical ventilation, extracorporeal gas exchange techniques are sometimes used in experienced centers (best results are seen in influenza-associated severe ARDS in relatively young patients).

Other rescue therapies remain unproven. In particular, high-frequency oscillatory ventilation has been used as a rescue therapy; however, when used early, it is not superior to low-tidal volume ventilation and may cause harm.Evidence 10Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Goligher EC, Munshi L, Adhikari NKJ, et al. High-Frequency Oscillation for Adult Patients with Acute Respiratory Distress Syndrome. A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 2017 Oct;14(Supplement_4):S289-S296. doi: 10.1513/AnnalsATS.201704-341OT. Review. PubMed PMID: 29043832. The use of nitric oxide is also controversial, with most recent reviews and practice guidelines suggesting that it should not be used.Evidence 11Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Griffiths MJD, McAuley DF, Perkins GD, et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Respir Res. 2019 May 24;6(1):e000420. doi: 10.1136/bmjresp-2019-000420. eCollection 2019. PubMed PMID: 31258917; PubMed Central PMCID: PMC6561387.

TablesTop