What Works in a Patient With Acute Respiratory Distress Syndrome?

INTRODUCTION

Acute respiratory distress syndrome (ARDS) was first recognized in the 1960s, when Ashbaugh et al. described a clinical constellation of hypoxemic respiratory failure accompanied by loss of pulmonary compliance and the histologic hallmark of alveolar hyaline membranes. From the first case series it was noted that a wide range of pulmonary insults incited a similar pathophysiology characterized by noncardiogenic pulmonary edema with diffuse, inflammatory alveolar injury. Markers of lung permeability, inflammation, and hyaline membrane formation are not routinely measured, however, and diagnosis focuses on clinical features and imaging findings. In 1992, the American-European consensus conference recommended criteria based on acute timing of onset, hypoxemia (Pa o ₂ :Fi o ₂ < 200 mm Hg for ARDS and < 300 mm Hg for acute lung injury), pulmonary consolidation represented by bilateral infiltrates on chest radiography, and absence of cardiogenic pulmonary edema as demonstrated by a pulmonary artery wedge pressure of less than 18 mm Hg.

The Berlin criteria published in 2012 refined these diagnostic features and remains the standard clinical definition of ARDS used today. Similar to the earlier consensus guidelines, it identified ARDS by the presence of hypoxemia and bilateral opacities on chest imaging consistent with noncardiogenic pulmonary edema, which manifest within 7 days of a known clinical insult or new or worsening respiratory symptoms ( Table 55.1 ). It clarified the previous consensus guidelines by 1) specifying the time frame of an acute onset, 2) establishing a minimum level of positive end expiratory pressure (PEEP) before the diagnosis of hypoxemia was made, 3) expanding imaging modalities to identify bilateral consolidations from just chest radiographs to include computed tomography (CT), and 4) removing the requirement for pulmonary artery wedge pressure (PAWP) to establish noncardiogenic edema. The Berlin definition also risk stratified patients into groups based on their degree of hypoxemia with a minimum level of ventilatory support into mild (200 mm Hg < Pa o ₂ :Fi o ₂ ≤ 300 mm Hg), moderate (100 mm Hg < Pa o ₂ :Fi o ₂ ≤ 200 mm Hg), and severe (Pa o ₂ :Fi o ₂ ≤ 100mm Hg) ARDS. Increasing severity of ARDS correlated with a rise in mortality.

Numerous conditions that result in either direct or indirect pulmonary injury can incite ARDS ( Table 55.2 ). The most common etiologies include nonpulmonary sepsis, viral or bacterial pneumonia, aspiration of gastric contents, and major trauma, including blunt or penetrating injury and burns. The high incidence of respiratory failure seen in intensive care unit (ICU) patients affected by the novel coronavirus 19 (COVID-19) has brought increasing attention to the role of an immunologic response to viral pneumonia in precipitating ARDS. Other frequently recognized insults include pancreatitis, pulmonary contusion, amniotic fluid and fat emboli, transfusion associated lung injury, and particle inhalation. The likelihood of developing ARDS varies with the predisposing insult. One prospective observational study in mechanically ventilated patients found that only 3% of patients with pancreatitis developed ARDS, whereas 26% of patients with smoke inhalation progressed to ARDS. ICU patients often develop multiple predisposing insults, which increase the risk for developing ARDS. Likewise, preexisting comorbidities can increase a patient’s risk for ARDS, including hypoalbuminemia, cigarette smoking, ^, and alcohol abuse.

These diverse etiologies create a similar pathophysiology that progresses through characteristic phases of injury, repair, and fibrosis. In the acute, exudative phase over days 1 to 7, lung microvascular injury disrupts the barrier function of the endothelium. Neutrophil-mediated endothelial injury is the most clearly documented pathway. Activated neutrophils extravasate into the alveolar space to release proinflammatory factors, including oxidants, proteases, leukotrienes, and platelet-activating factor that injure the epithelium. The combination of damage to both endothelium and epithelium increases alveolar permeability. A proteinaceous pulmonary edema containing neutrophils, macrophages, sloughed epithelial cells, and hyaline membranes accumulates in the alveoli and lung interstitium on the denuded basement membrane. Alveolar macrophages release proinflammatory cytokines, such as IL-1, -6, -8, -10, and tumor necrosis factor (TNF)-α, which, in turn, stimulate neutrophil chemotaxis and activation. The alveolar edema inactivates surfactant, resulting in atelectasis. Over the subacute phase in days 7 to 14, repair begins with the proliferation of alveolar type II epithelial cells, squamous metaplasia, and the resorption of some edema. At this stage, fibroblasts begin to infiltrate, and there may be evidence of collagen deposition. Some patients progress to a third, chronic phase characterized by extensive fibrosis, which can result in cyst formation and destruction of lung parenchyma.

Calculating the incidence of ARDS has been limited by its evolving definition and underrecognition in the clinical setting. One important complication in estimating its incidence remains regional variability in ICU resources that make it difficult to differentiate between a true distinction in disease incidence and a disparity in ICU bed allocation. These caveats may partially explain the wide discrepancy in reported incidences, which range from 3.65 cases in Iceland to 71 cases in the United States per 100,000 person years. ^,

The LUNG SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) study provided a recent analysis of ARDS epidemiology through a prospective, multicenter, observational design conducted on more than 29,000 ICU patients in 50 countries. The study found that 10% of ICU patients and 23% of mechanically ventilated patients met the diagnostic criteria for ARDS. Mortality increased with the severity of ARDS, ranging from 35% in mild ARDS to 40% for moderate ARDS and 46% in severe ARDS. The causative insult also impacted hospital mortality. Patients with ARDS secondary to trauma had a 24% mortality, whereas ARDS caused by sepsis with a pulmonary source carried a 40.6% mortality. This wide range emphasizes that mortality associated with ARDS may not be mortality caused by ARDS but rather reflect comorbidities such as nonpulmonary organ system dysfunction, immunosuppression, shock, and malignancy. A subsequent analysis of the LUNG SAFE patient data found that hospital mortality in immunocompromised patients was significantly higher than in immunocompetent patients (52% vs. 36%).

A key finding of the LUNG SAFE analysis was the underdiagnosis of ARDS by clinicians; only 51% of mild ARDS and 79% of severe ARDS cases were identified. Congruent with this, the study determined that less than two-thirds of patients with ARDS received lung protective ventilation with low tidal volumes (≤ 8 cc/kg), and plateau pressure was measured in less than half. Recognition of ARDS was associated with implementation of established supportive therapies, including higher PEEP, prone positioning, and neuromuscular blockade.

TREATMENT

Treatment of ARDS focuses on lung protective respiratory support that optimizes gas exchange while minimizing ventilator-induced lung injury (VILI). The inciting cause(s) should be identified and addressed, including cultures of infectious sources with a low threshold for empiric antibiotics. Standard ICU supportive care such as enteral nutrition, stress ulcer prophylaxis, and venous thrombosis prophylaxis should be provided. Formal guidelines on management of ARDS suggest an initial stabilization phase that starts with optimization of mechanical ventilation and proceeds to implement additional treatments if the patient does not respond to this first-line measure.

CURRENT THERAPIES