Acute Respiratory Distress Syndrome

Abstract

Acute Respiratory Distress Syndrome (ARDS) is defined as the rapid onset of non-cardiogenic pulmonary edema resulting in respiratory failure and hypoxemia. Efforts over the past 25 years, such as those of the ARDS and Prevention and Early Treatment of Acute Lung Injury (PETAL) Networks, have demonstrated a praiseworthy collaboration to further optimize the management of ARDS. However, improvements have been only moderate and ARDS remains a leading cause of mortality in the perioperative and critical care setting. Recently, the significant morbidity and mortality of ARDS have been emphasized by its high incidence in Coronavirus Disease 2019 (COVID-19) patients. A major hurdle to reducing ARDS mortality is that current treatment is limited to preventive measures – such as the use of lung-protective ventilation. Therapeutic approaches targeting the underlying inflammatory lung disease are areas of intensive research, but have not been clinically implemented. Nevertheless, basic science and clinical research efforts that are aimed at identifying novel treatment approaches and further improving outcomes for ARDS are ongoing. Here, we review evidence-based management approaches for ARDS, while highlighting those being investigated or heavily utilized in ARDS associated with COVID-19.

Figure 1:

A summary of 25 years of Acute Respiratory Distress Syndrome (ARDS) intervention trials. Interventions are chronologically displayed with corresponding clinical trials italicized underneath and color-coded to denote clinical efficacy. Interventions that have clear clinical efficacy, in blue boxes, include the use of small tidal volumes, prone positioning, and restrictive fluid administration, which have demonstrated clear mortality or ventilator-free days benefits. Interventions in grey boxes include those that have mixed results from different trials, as is the case for conservative oxygen treatment^,, and early neuromuscular blockade.^, This category (grey boxes) also includes interventions with indeterminate results, such as the case for Positive End Expiratory Pressure (PEEP) – itself is a component of lung-protective ventilation, but the appropriate amount to use is still contended – or those that have value in ARDS patients aside from improving ARDS outcomes, such as early trophic enteral nutrition to prevent gastric intolerance and Extracorporeal Membrane Oxygenation (ECMO) as a rescue therapy.^, In orange boxes are interventions that failed to demonstrate improvements in ARDS outcomes, such as antifungals, lisofylline, albuterol, simvastatin, vitamin C and vitamin D.^– Dexamethasone is also listed in this category given that the DEXA-ALI trial was conducted in an unblinded fashion and prior randomized trials showed no clinical efficacy for steroid administration in ARDS. Methylprednisolone, rosuvastatin and ω−3 Fatty Acids, listed in red boxes, have shown to cause potential harm in randomized controlled trials. Currently, ongoing or planned trials and emerging therapeutic targets are displayed in green.

Figure 2.

Pathophysiology of Acute Respiratory Distress Syndrome (ARDS) in Coronaviruas Disease 2019 (COVID-19). SARS-CoV-2 infection is mediated by virus spike binding to angiotensin converting enzyme-2 (ACE2) on type 2 alveolar epithelial cells.^, Viral infection prompts cells to react by releasing chemokines and cytokines. Infection can also overwhelm epithelial cells and cause them to die via pyroptosis, which results in the release of inflammatory Damage and Pathogen Associated Molecular Patterns (DAMPs/PAMPs). Recognition of PAMPs/DAMPs and cytokines activates alveolar macrophages and chemokines act to recruit inflammatory immune cells to the lung. Excessive immune cell release of antimicrobial effectors, such as metallomatrix proteases (MMPs), elastases, and reactive oxygen species (ROS), induce collateral tissue injury that results in loss of epithelial and endothelial barrier integrity and infiltration of proteinaceous fluid into the alveolar airspace. Furthermore, increasing evidence supports the important role of endothelial cells in the initiation of inflammation and the development of extensive pulmonary intravascular coagulopathy that is common in COVID-19 patients.^– In severe cases, patients with COVID-19 have developed disseminated intravascular coagulopathy.