Acute Respiratory Distress Syndrome: Contemporary Management and Novel Approaches During COVID-19

George W. Williams, M.D.; Nathaniel K. Berg, B.S.; Alexander Reskallah, M.D.; Xiaoyi Yuan, Ph.D.; Holger K. Eltzschig, M.D., Ph.D.


Anesthesiology. 2021;134(2):270-282. 

In This Article

Clinical Treatment Concepts

Nationally Organized Research Consortia to Study ARDS

To improve outcomes and develop treatment protocols for ARDS, the National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, Maryland) funded a series of multicenter clinical trials, which formed a research collaboration called the ARDS Network (, accessed July 22, 2020).[7] Beginning in 1994, the network studies enrolled more than 5,500 patients, included 10 clinical trials and one observational study, led to the development of new clinical parameters such as ventilator-free days,[8] and resulted in seminal advances that have helped to shape current ARDS management. National Heart, Lung, and Blood Institute–funded clinical trials continue currently under the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network (, accessed July 22, 2020). Figure 1 and Table 1 briefly summarize the results and implications of the results for ARDS and PETAL Network trials, along with other important trials performed internationally.

Figure 1.

A summary of 25 yr 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,9 prone positioning,20 and restrictive fluid administration,37 which have demonstrated clear mortality or ventilator-free days benefits. Interventions in gray boxes include those that have mixed results from different trials, as is the case for conservative oxygen treatment32,33,75 and early neuromuscular blockade.38,39 This category (gray boxes) also includes interventions with indeterminate results, such as the case for positive end-expiratory pressure (PEEP)15 —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 intolerance40 and extracorporeal membrane oxygenation as a rescue therapy.35,36 In orange boxes are interventions that failed to demonstrate improvements in ARDS outcomes, such as antifungals, lisofylline, albuterol, simvastatin, vitamin C, and vitamin D.41–47,76,77 Dexamethasone is also listed in this category given that the DEXA-ARDS trial was conducted in an unblinded fashion28 and previous randomized trials showed no clinical efficacy for steroid administration in ARDS. Methylprednisolone,27 rosuvastatin,49 and omega-3 fatty acids,48 listed in red boxes, have been shown to cause potential harm in randomized controlled trials. Current, ongoing, or planned trials and emerging therapeutic targets are displayed in green.

Small Tidal Volumes

Among the best-established guidelines in managing ARDS patients is the use of small tidal volumes during mechanical ventilation (Figure 1). In 2000, investigators from the ARDSNet Lower Tidal Volume (ARMA) trial reported significantly decreased rates of mortality (31.0% vs. 39.8%) in ARDS patients ventilated with 6 ml/kg of predicted body weight tidal volumes versus those with 12 ml/kg of predicted body weight.[9] While small tidal volume ventilation remains a tenet of lung-protective ventilation during ARDS, recent efforts have sought to determine whether small tidal volumes play a lung-protective role more broadly in all critically ill ventilated patients. In 2018, the Protective Ventilation in Patients Without ARDS (PReVENT) trial indicated that ventilation with low tidal volumes may not be more effective than intermediate volumes in non-ARDS intensive care unit patients.[10]

Positive End-expiratory Pressure

In their seminal 1967 report of ARDS cases, Ashbaugh et al. reported that improvement of hypoxemia and atelectasis was achieved by the implementation of positive end-expiratory pressure (PEEP).[11] Since then, PEEP continues to be employed in ARDS management and remains the focus of many clinical research efforts. Conceptually, PEEP is administered in order to reduce atelectrauma (repetitive opening and closing of alveoli) by recruiting collapsed alveoli.[12] Much attention has been directed at the levels at which PEEP is applied, with clinical evidence yielding mixed results (Figure 1). Several trials that report protective benefits from higher versus lower targets of PEEP employed higher tidal volumes in their control (lower PEEP) groups, which perhaps introduced bias in their conclusions.[13,14] Trials that have controlled for low tidal volumes (6 ml/kg), including the 2004 ARDS Network Higher vs Lower PEEP (ALVEOLI) trial, have failed to establish a survival benefit for higher PEEP.[15,16] Subgroup analysis does, however, suggest that higher PEEP is associated with improved survival among the subgroup of patients with ARDS who objectively respond to increased PEEP (patients who show improved oxygenation in response to increased PEEP).[17] Still, it has yet to be demonstrated whether survival in selected patients improves with increased PEEP in large randomized trials.

Prone Positioning

Beneficial effects of prone positioning during mechanical ventilation of ARDS patients are considered in order to establish a more even distribution of gravitational force in pleural pressure, allowing for improved ventilation of the dorsal lung space[18] and limiting overdistention of alveoli.[19] In 2013, Guérin et al. reported the results of the Proning Severe ARDS Patients (PROSEVA) trial in which severe ARDS patients (PaO 2/fractional inspired oxygen tension [FIO 2] less than 150 on FIO 2 of at least 0.6) were randomized to prone positioning for a minimum of 16 h/day.

Patients randomized to prone positioning had a 50% reduction in mortality (16% vs. 32.8%) at 28 days (Figure 1).[20] A recent meta-analysis corroborates these results and supports the survival benefits of prolonged prone positioning (greater than 12 h) in patients with severe ARDS.[21] Despite these encouraging results in reducing mortality with the use of prone positioning, data from a large, multinational prospective observational study indicate that the maneuver was employed in only 16.3% of severe ARDS patients.[2] Possible reasons for this low implementation could be attributed to the relative complexity and logistic considerations of prone positioning (e.g., multiple persons required for the maneuver, increased workloads, management of secretions, and nutrition) or to the inherent risks of the procedure such as endotracheal tube and vascular line displacement. Nonetheless, the use of prone positioning for more than 12 h/day remains a strong recommendation for patients with severe ARDS.[22]

Although the efficacy of prone positioning is almost exclusively suggested in patients with PaO2/FIO2 ratios of 150 or less, trials that failed to show efficacy in mild and moderate ARDS are largely underpowered and failed to administer prone positioning for recommended lengths of time.[23] As such, randomized trials implementing early prone positioning in mild to moderate cases of ARDS are necessary to determine any survival benefits and to make recommendations for clinical implementation.

Steroids in Non–COVID-19 ARDS

In the report of ARDS patients by Ashbaugh et al. in 1967, it was suggested that corticosteroids appeared to have clinical value in cases associated with fat emboli and viral pneumonia.[11] Randomized control trials conducted in the 1980s have since demonstrated that early administration of methylprednisolone did not result in improved ARDS survival.[24,25] However, in 1998 a prospective trial by Meduri et al. showed an improved outcome in ARDS patients treated with prolonged methylprednisolone.[26] The results of the study were subject to scrutiny due to the small sample size (n = 8) of the control group, significant crossover into the methylprednisolone group (all of whom died), and a relatively large mortality rate of 60%. Subsequently, in 2006 the ARDS Network addressed the role of corticosteroid administration late in ARDS with the Late Steroid Rescue Study (LaSRS) in which 180 patients were randomized to methylprednisolone administration 7 to 28 days after diagnosis of ARDS. Administration of methylprednisolone was not linked with significant reduction in mortality (Figure 1).[27] Furthermore, patients who started steroid treatment after 14 days of diagnosis experienced increased mortality.

Based on the postulate that, compared to other corticosteroids, dexamethasone has an improved potency, lengthened duration of action, and weak mineralocorticoid effect, Villar et al. performed a prospective trial randomizing ARDS patients to receive either dexamethasone or placebo.[28] Compared to patients in the control group, the dexamethasone treatment group showed a reduced time on mechanical ventilation and 60-day mortality; however, drug allocation and data analysis were performed in an unblinded fashion, potentially leading to bias. Furthermore, 250 patients were excluded for already receiving steroids before randomization, indicating that participating physicians already favored the use of corticosteroids, which might have influenced clinical decisions to modify mechanical ventilation duration. In summary, guidelines supporting routine glucocorticoid administration in ARDS based on rigorously performed randomized controlled trials are currently not supporting their use. However, as discussed later in this review in the section of "Steroids in COVID-19 ARDS", dexamethasone treatment has been the first therapy to show mortality improvement in mechanically ventilated COVID-19 patients.[29]

Conservative Oxygenation

Among the most common therapies implemented in critically ill patients and nearly all ARDS patients is the supplemental provision of oxygen. Oxygen is frequently delivered generously in order to increase PaO2, and oftentimes patients become hyperoxic while attempting to reverse tissue hypoxia. However, evidence indicates that liberal oxygen use is associated with vasoconstriction, decreased cardiac output, absorption atelectasis, increased proinflammatory responses, and increased mortality.[30,31] As such, establishing a protocol of oxygen treatment that balances essential delivery to organs while preventing excessive harmful effects of hyperoxia has been an important subject of recent investigations (Figure 1). In a single-center randomized trial published in 2016, critically ill intensive care unit patients with a length of stay of 3 days or longer who were assigned to receive conservative oxygen therapy (PaO2 between 70 and 100 mmHg) had lower mortality than those who received more conventional care (PaO2 up to 150 mmHg).[32] A more recent study, the 2020 Liberal Oxygenation versus Conservative Oxygenation in Acute Respiratory Distress Syndrome (LOCO2) trial, Barrot et al. recruited ARDS patients to conservative (oxygen saturation measured by pulse oximetry [SpO2] between 88 and 92%) or liberal (SpO2 greater than 96%) oxygen treatment arms. The trial was terminated early due to an associated increase in mortality at 28 days and five episodes of mesenteric ischemia in the conservative oxygen treatment group.[33] Worse outcomes in conservative oxygenation may be attributed to the deteriorated gas exchange in ARDS patients, making them more prone to hypoxemia in the conservative oxygen treatment arm. Going forward, trials will need to carefully assess how to determine target oxygenation levels (e.g., SpO 2 and PaO 2 targets, measurements from mixed venous blood, different targets for different organ injuries) to better answer how oxygen concentrations are selected.

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation is a rescue therapy that has been employed in ARDS patients who fail to improve on mechanical ventilation management and as a means to avoid potential injurious aspects of ventilator-associated lung injury. Advances in extracorporeal membrane oxygenation delivery have been associated with an increase in the number of centers and cases using it, particularly since the 2009 influenza A virus subtype (H1N1) influenza pandemic.[34] Investigators from the 2009 Conventional Ventilatory Support versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial group sought to answer whether the use of extracorporeal membrane oxygenation during severe ARDS would provide a survival benefit when compared to conventional support by mechanical ventilation (Figure 1).[35] The results of the trial indicated that there was a survival benefit in favor of patients being randomized to extracorporeal membrane oxygenation treatment, but this difference was not statistically significant. Furthermore, the study was impaired by the use of heterogeneous mechanical ventilation strategies in the control group (including the use of large tidal volumes). Additionally, a large percentage of patients in the extracorporeal membrane oxygenation group who were transferred to extracorporeal membrane oxygenation–capable hospitals never received extracorporeal membrane oxygenation, allowing for the potential confounding effects attributed to the fact that extracorporeal membrane oxygenation–capable hospitals may attain enhanced ARDS survival regardless of whether patients actually received extracorporeal membrane oxygenation. A subsequent international multicenter study was conducted to specifically address weaknesses of previous trials implementing extracorporeal membrane oxygenation in early severe ARDS, the 2018 ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial.[36] Despite achieving a high quality of control for ventilation strategies in both groups and nearly universal implementation of extracorporeal membrane oxygenation in patients randomized to receive it, the results demonstrated that there was no significant difference in mortality between the extracorporeal membrane oxygenation group and the control group. Given the lack of strong evidence supporting the use of extracorporeal membrane oxygenation as a routine early treatment for ARDS, it is recommended that extracorporeal membrane oxygenation is reserved as rescue therapy in patients who remain hypoxemic despite conventional evidence-based approaches.

Other Investigated Therapeutic Approaches

A large number of pharmacologic approaches have been tested in large, randomized controlled trials in order to improve clinical outcomes in patients with ARDS. These trials have included approaches such as the use of β2-adrenergics, ketoconazole, lisofylline, vitamin C and D, omega fatty acids, restrictive fluid administration, and statins (Figure 1 and Table 1).[37–49] Although none of these trials have demonstrated a mortality benefit in ARDS patients, it should be highlighted that recent advancements in our understanding of ARDS pathophysiology indicate that there are likely important subtypes of injury that predict beneficial response to particular therapies.[50] Appropriate identification and selection of patients with specific subphenotypes of ARDS may allow for a targeted approach to effective treatments and more efficient clinical trials.