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Acute Respiratory Distress Syndrome Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Seminar Acute respiratory distress syndrome Nuala J Meyer, Luciano Gattinoni, Carolyn S Calfee Acute respiratory distress syndrome (ARDS) is an acute respiratory illness characterised by bilateral chest Published Online radiographical opacities with severe hypoxaemia due to non-cardiogenic pulmonary oedema. The COVID-19 July 1, 2021 pandemic has caused an increase in ARDS and highlighted challenges associated with this syndrome, including its https://doi.org/10.1016/ S0140-6736(21)00439-6 unacceptably high mortality and the lack of effective pharmacotherapy. In this Seminar, we summarise current Pulmonary, Allergy and Critical knowledge regarding ARDS epidemiology and risk factors, differential diagnosis, and evidence-based clinical Care Division, University of management of both mechanical ventilation and supportive care, and discuss areas of controversy and ongoing Pennsylvania School of research. Although the Seminar focuses on ARDS due to any cause, we also consider commonalities and distinctions Medicine, Philadelphia, PA, of COVID-19-associated ARDS compared with ARDS from other causes. USA (Prof N J Meyer MD); Department of Anesthesiology, Intensive Care and Emergency Introduction Given that many patients with diffuse lung injury Medicine, University Medical Acute respiratory distress syndrome (ARDS) is the acute supported with high-flow nasal cannula (HFNC) do not Center Göttingen, Göttingen, onset of hypoxaemia and bilateral pulmonary oedema meet the ARDS Berlin definition, which requires Germany (Prof L Gattinoni MD); Division of Pulmonary, Critical 1 due to excessive alveolocapillary permeability. Although positive pressure ventilation, the incidence of ARDS is Care, Allergy and Sleep ARDS has a codified clinical definition, known as the probably even higher. The COVID-19 pandemic has Medicine, Departments of Berlin definition (panel 1) with stages that estimate highlighted this limitation, as many patients are treated Medicine and Anesthesia, mortality risk,1 there is no single test to identify or exclude without mechanical ventilation.7,8 Men might be slightly University of California San Francisco, San Francisco, the diagnosis. The heterogeneity of ARDS, evident in more likely to develop ARDS, although outcome is CA, USA (Prof C S Calfee MD) 2,3 9 its causes, manifestations, and response to therapy, largely similar between sexes. Women—and patients of Correspondence to: challenges clinicians and scientists to provide impeccable shorter stature—are less likely to receive lung protective Prof Nuala J Meyer, Pulmonary, supportive care and discover new therapies. This Seminar ventilator tidal volumes.10 For patients with severe Allergy and Critical Care Division, summarises current knowledge regarding ARDS persistent ARDS, women had higher mortality than University of Pennsylvania Perelman School of Medicine, 11 epide miology and risk factors, differential diagnosis, and men. Black patients might have a reduced risk of Philadelphia, PA 19096, USA clinical management, and highlights controversial topics developing ARDS,9 and Black and Hispanic patients nuala.meyer@pennmedicine. and ongoing research. This Seminar also includes a with ARDS had a higher mortality in at least one study, upenn.edu section on the COVID-19 pandemic and ARDS. which seemed to be mediated by increased severity of illness.12 Tobacco use, alcohol use, hypoalbuminaemia, Epidemiology and outcomes chemotherapy within the previous 6 months, and ARDS is more common than initially believed. In 2016, ambient air pollutant exposure4,13–16 can increase ARDS a study of patients in 459 intensive care units (ICUs) risk, whereas, in some studies, patients with diabetes from 50 countries reported that 10% of ICU patients and were less likely to develop ARDS.17,18 23% of mechanically ventilated patients fulfilled criteria for ARDS.4 Although the survey was done during the winter viral season and included ARDS that resolved Panel 1: The Berlin definition of ARDS and observed rapidly,5 the hospital mortality of 35–45% closely mortality1 resembled that described by the large datasets used to validate the Berlin definition.1,4 Even patients whose • Acute onset (within 7 days of new or worsening respiratory symptoms) ARDS resolved rapidly had a mortality rate of 31%.6 • Bilateral radiographical opacities that are not fully explained by effusion, atelectasis, or masses Search strategy and selection criteria • Arterial hypoxaemia defined by thresholds: • Mild: 200 < PaO2/FiO2 ratio ≤300 mm Hg, on CPAP* or We searched PubMed from database inception to PEEP† ≥5 cm H₂O (observed mortality 27%) Dec 14, 2020, using the search terms "Acute Respiratory • Moderate: 100 < PaO2/FiO2 ratio ≤200 mm Hg, Distress Syndrome", "ARDS", "acute lung injury", "positive end on PEEP ≥5 cm H₂O (observed mortality 32%) expiratory pressure", "COVID-19", "SARS-CoV-2", "prone • Severe: PaO2/FiO2 ratio ≤100 mm Hg, on PEEP ≥5 cm position", and "neuromuscular blockade". The search was H₂O (observed mortality 45%) limited to studies of humans. Returned lists of articles were • Identified risk factor for ARDS (if no clear risk factor, then screened manually by reading abstracts to exclude exclude heart failure as a cause) neonatal lung injury and neonatal respiratory distress • Not exclusively due to cardiac causes syndrome. Comprehensive reviews that have been published within the past 3 years were also read in full, and their ARDS=acute respiratory distress syndrome. CPAP=continuous positive pressure ventilation. FiO₂=fraction of inspired oxygen. PaO2=partial pressure of oxygen. reference lists were reviewed. Remaining manuscripts were PEEP=positive end-expiratory pressure. *CPAP delivered by non-invasive or invasive read in full and their references reviewed when appropriate. ventilation. †PEEP delivered by invasive mechanical ventilation. www.thelancet.com Published online July 1, 2021 https://doi.org/10.1016/S0140-6736(21)00439-6 1 Seminar functional limitations related to muscle weakness, Panel 2: Classic precipitants of ARDS deconditioning, or psychological sequelae of severe 22,23 Common precipitants illness. Cognitive impairment is also distressingly 24,25 • Pneumonia (bacterial and viral are the most common, common, affecting almost half of survivors at 2 years. whereas fungal, mycobacterial, and parasitic pneumonia are less common) Causes and risk factors 26 • Non-pulmonary sepsis Since its initial description, ARDS has been recognised • Aspiration of gastric contents as a clinical condition that develops in the setting of • Non-cardiogenic shock various causes or risk factors (panel 2). The most common • Pancreatitis risk factors are pneumonia and non-pulmonary sepsis, 4,27 • Severe trauma or high-risk surgery (eg, esophagectomy) followed by aspiration of gastric contents. Trauma and • Drug overdose blood product transfusion are less common ARDS risk • Ischaemia-reperfusion injury factors in the modern era as ventilator, fluid, and transfusion management has evolved,4,28 whereas new Less common precipitants causes such as e-cigarette or vaping product use- • Smoke inhalation associated lung injury (EVALI) have emerged.29,30 Bacterial • Drowning and viral pneumonias frequently cause ARDS, with • Vape or e-cigarette use sporadic spikes in global ARDS incidence due to • Multiple transfusion of blood products pandemic influenza31 and emerging viruses including 32,33 Diagnoses not typically classified as ARDS SARS-CoV-2 and the coronaviruses responsible for 34 35,36 • Vasculitis SARS and MERS. Identification of a specific cause for • Diffuse alveolar haemorrhage ARDS remains a crucial therapeutic goal to improve 37 • Drug-induced pneumonitis outcomes associated with ARDS. Although genetic • Organising pneumonia susceptibility to ARDS is suggested by the variability with • Hypersensitivity pneumonitis which clinical risk factors predict ARDS development and • Acute eosinophilic pneumonia by the replicated association of numerous genetic variants 38,39 • Acute exacerbation of interstitial lung disease with ARDS risk, the attributable risk of any singular • Acute chest syndrome (ie, sickle cell disease) genetic polymorphism to ARDS risk or outcome seems • Alveolar proteinosis small. • Malignancy ARDS=acute respiratory distress syndrome. Diagnostic considerations No single diagnostic test confirms or refutes a diagnosis of ARDS. Furthermore, it must be emphasised that A B ARDS is a syndrome rather than a specific pathologic entity and is currently identified by purely clinical criteria. As elaborated by the Berlin definition,1 ARDS diagnosis requires that new or worsening respiratory distress and bilateral chest radiographical abnormalities be present for 7 days or fewer, that heart failure cannot fully explain the hypoxaemia and
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