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Since its first description 50 years ago, no other intensive care syndrome has been as extensively studied as acute respiratory distress syndrome (ARDS). Despite this extensive body of research, many basic epidemiologic questions remain unsolved. The lack of gold standard tests jeopardizes accurate diagnosis and translational research. Wide variation in the population incidence has been reported, making even simple estimates of the burden of disease problematic. Despite these limitations, there has been an increase in the understanding of pathophysiology and important risk factors both for the development of ARDS and for important patient-centered outcomes like mortality. In this Critical Care Perspective, we discuss the historical context of ARDS description and attempts at its definition. We highlight the epidemiologic challenges of studying ARDS, as well as other intensive care syndromes, and propose solutions to address them. We update the current knowledge of ARDS trends in incidence and mortality, risk factors, and recently described endotypes.

This month marks the 50th anniversary of the first description of the condition now termed the acute respiratory distress syndrome, or ARDS. The authors of this review discuss our current understanding of the pathobiology and treatment of ARDS.

Influenza virus affects the respiratory tract by direct viral infection or by damage from the immune system response. In humans, the respiratory epithelium is the only site where the hemagglutinin (HA) molecule is effectively cleaved, generating infectious virus particles. Virus transmission occurs through a susceptible individual’s contact with aerosols or respiratory fomites from an infected individual. The inability of the lung to perform its primary function of gas exchange can result from multiple mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity from direct epithelial cell killing, and degradation of the critical extracellular matrix. Approximately 30–40% of hospitalized patients with laboratory-confirmed influenza are diagnosed with acute pneumonia. These patients who develop pneumonia are more likely to be < 5 years old, > 65 years old, Caucasian, and nursing home residents; have chronic lung or heart disease and history of smoking, and are immunocompromised. Influenza can primarily cause severe pneumonia, but it can also present in conjunction with or be followed by a secondary bacterial infection, most commonly by Staphylococcus aureus and Streptococcus pneumoniae . Influenza is associated with a high predisposition to bacterial sepsis and ARDS. Viral infections presenting concurrently with bacterial pneumonia are now known to occur with a frequency of 30–50% in both adult and pediatric populations. The H3N2 subtype has been associated with unprecedented high levels of intensive care unit (ICU) admission. Influenza A is the predominant viral etiology of acute respiratory distress syndrome (ARDS) in adults. Risk factors independently associated with ARDS are age between 36 and 55 years old, pregnancy, and obesity, while protective factors are female sex, influenza vaccination, and infections with Influenza A (H3N2) or Influenza B viruses. In the ICU, particularly during the winter season, influenza should be suspected not only in patients with typical symptoms and epidemiology, but also in patients with severe pneumonia, ARDS, sepsis with or without bacterial co-infection, as well as in patients with encephalitis, myocarditis, and rhabdomyolysis.

Purpose Experimental animal models of acute respiratory distress syndrome (ARDS) have shown that the updated airway pressure release ventilation (APRV) methodologies may significantly improve oxygenation, maximize lung recruitment, and attenuate lung injury, without circulatory depression. This led us to hypothesize that early application of APRV in patients with ARDS would allow pulmonary function to recover faster and would reduce the duration of mechanical ventilation as compared with low tidal volume lung protective ventilation (LTV). Methods A total of 138 patients with ARDS who received mechanical ventilation for <48 h between May 2015 to October 2016 while in the critical care medicine unit (ICU) of the West China Hospital of Sichuan University were enrolled in the study. Patients were randomly assigned to receive APRV ( n  = 71) or LTV ( n  = 67). The settings for APRV were: high airway pressure (P high ) set at the last plateau airway pressure (P plat ), not to exceed 30 cmH 2 O) and low airway pressure ( P low ) set at 5 cmH 2 O; the release phase (T low ) setting adjusted to terminate the peak expiratory flow rate to ≥ 50%; release frequency of 10–14 cycles/min. The settings for LTV were: target tidal volume of 6 mL/kg of predicted body weight; P plat not exceeding 30 cmH 2 O; positive end-expiratory pressure (PEEP) guided by the PEEP–FiO 2 table according to the ARDSnet protocol. The primary outcome was the number of days without mechanical ventilation from enrollment to day 28. The secondary endpoints included oxygenation, P plat , respiratory system compliance, and patient outcomes. Results Compared with the LTV group, patients in the APRV group had a higher median number of ventilator-free days {19 [interquartile range (IQR) 8–22] vs. 2 (IQR 0–15); P  < 0.001}. This finding was independent of the coexisting differences in chronic disease. The APRV group had a shorter stay in the ICU ( P  = 0.003). The ICU mortality rate was 19.7% in the APRV group versus 34.3% in the LTV group ( P  = 0.053) and was associated with better oxygenation and respiratory system compliance, lower P plat , and less sedation requirement during the first week following enrollment ( P  < 0.05, repeated-measures analysis of variance). Conclusions Compared with LTV, early application of APRV in patients with ARDS improved oxygenation and respiratory system compliance, decreased P plat and reduced the duration of both mechanical ventilation and ICU stay.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are a continuum of lung changes arising from a wide variety of lung injuries, frequently resulting in significant morbidity and frequently in death. Research regarding the molecular pathophysiology of ALI/ARDS is ongoing, with the aim toward developing prognostic molecular biomarkers and molecular-based therapy. To review the clinical, radiologic, and pathologic features of ALI/ARDS; and the molecular pathophysiology of ALI/ARDS, with consideration of possible predictive/prognostic molecular biomarkers and possible molecular-based therapies. Examination of the English-language medical literature regarding ALI and ARDS. ARDS is primarily a clinicoradiologic diagnosis; however, lung biopsy plays an important diagnostic role in certain cases. A significant amount of progress has been made in the elucidation of ARDS pathophysiology and in predicting patient response, however, currently there is no viable predictive molecular biomarkers for predicting the severity of ARDS, or molecular-based ARDS therapies. The proinflammatory cytokines TNF-α (tumor necrosis factor α), interleukin (IL)-1β, IL-6, IL-8, and IL-18 are among the most promising as biomarkers for predicting morbidity and mortality.

This analysis of previously reported trials shows that low tidal volumes, a key component of safer ventilation strategies, confer a protective effect against complications only if the lower volume results in a lower pulmonary driving pressure. Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (V T ), and higher positive end-expiratory pressures (PEEPs) — collectively termed lung-protective strategies — have been associated with survival benefits in randomized clinical trials involving patients with the acute respiratory distress syndrome (ARDS). 1 – 4 The different components of lung protection in those strategies, such as lower V T , lower plateau pressure, and higher PEEP, can all reduce mechanical stresses on the lung, which are thought to induce ventilator-induced lung injury. 5 – 9 Clinical trials, however, have reported conflicting responses to the manipulation of separate components of lung . . .

The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.

Acute respiratory distress syndrome (ARDS) survivors experience a high prevalence of cognitive impairment with concomitantly impaired functional status and quality of life, often persisting months after hospital discharge. In this review, we explore the pathophysiological mechanisms underlying cognitive impairment following ARDS, the interrelations between mechanisms and risk factors, and interventions that may mitigate the risk of cognitive impairment. Risk factors for cognitive decline following ARDS include pre-existing cognitive impairment, neurological injury, delirium, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation, and environmental factors in the intensive care unit, which can co-occur synergistically in various combinations. Detection and characterization of pre-existing cognitive impairment imparts challenges in clinical management and longitudinal outcome study enrollment. Patients with brain injury who experience ARDS constitute a distinct population with a particular combination of risk factors and pathophysiological mechanisms: considerations raised by brain injury include neurogenic pulmonary edema, differences in sympathetic activation and cholinergic transmission, effects of positive end-expiratory pressure on cerebral microcirculation and intracranial pressure, and sensitivity to vasopressor use and volume status. The blood-brain barrier represents a physiological interface at which multiple mechanisms of cognitive impairment interact, as acute blood-brain barrier weakening from mechanical ventilation and systemic inflammation can compound existing chronic blood-brain barrier dysfunction from Alzheimer’s-type pathophysiology, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage. Although some contributory elements, such as the presenting brain injury or pre-existing cognitive impairment, may be irreversible, interventions such as minimizing mechanical ventilation tidal volume, minimizing duration of exposure to sedating medications, maintaining hemodynamic stability, optimizing fluid balance, and implementing bundles to enhance patient care help dramatically to reduce duration of delirium and may help prevent acquisition of long-term cognitive impairment.

Spontaneous respiratory effort during mechanical ventilation has long been recognized to improve oxygenation, and because oxygenation is a key management target, such effort may seem beneficial. Also, disuse and loss of peripheral muscle and diaphragm function is increasingly recognized, and thus spontaneous breathing may confer additional advantage. Reflecting this, epidemiologic data suggest that the use of partial (vs. full) support modes of ventilation is increasing. Notwithstanding the central place of spontaneous breathing in mechanical ventilation, accumulating evidence indicates that it may cause-or worsen-acute lung injury, especially if acute respiratory distress syndrome is severe and spontaneous effort is vigorous. This Perspective reviews the evidence for this phenomenon, explores mechanisms of injury, and provides suggestions for clinical management and future research.

Positive end-expiratory pressure (PEEP) is used to improve oxygenation in patients with acute lung injury or the acute respiratory distress syndrome. In this pilot trial, the investigators show that adjusting PEEP with the use of measurements of esophageal pressure to estimate transpulmonary pressure leads to improved oxygenation as compared with the conventional approach to ventilator management. Patients with acute lung injury or ARDS were randomly assigned to mechanical ventilation directed either by esophageal-pressure measurements or according to standard-of-care recommendations. The use of esophageal pressures to estimate the transpulmonary pressure significantly improved oxygenation and respiratory-system compliance. Recent changes in the practice of mechanical ventilation have improved survival in patients with the acute respiratory distress syndrome (ARDS), but mortality remains unacceptably high. Whereas low tidal volumes are clearly beneficial in patients with ARDS, how to choose a positive end-expiratory pressure (PEEP) is uncertain. 1 – 4 Ideally, mechanical ventilation should provide sufficient transpulmonary pressure (airway pressure minus pleural pressure) to maintain oxygenation while minimizing repeated alveolar collapse or overdistention leading to lung injury. 5 In critical illness, however, there is marked variability among patients in abdominal and pleural pressures 6 , 7 ; thus, for a given level of PEEP, transpulmonary pressures . . .