The Acute Respiratory Distress Syndrome

Clinical Principles Severe respiratory distress and 1 or more risk factors (including infection, aspiration, pancreatitis, and trauma) Impaired arterial oxygenation (hypoxemia) Bilateral pulmonary infiltrates on chest radiograph No clinical evidence of elevated left atrial pressure (or pulmonary artery occlusion pressure of 18 mm Hg if measurements are available) Physiologic Principles The cardinal feature of ARDS, refractory hypoxemia, is caused by formation of protein-rich alveolar edema after damage to the integrity of the lung's alveolar-capillary barrier. Alveolar-capillary damage in ARDS can be initiated by physical or chemical injury or by extensive activation of innate inflammatory responses. Such damage causes the lung's edema safety factor to decrease by about half, and edema develops at low capillary pressures. Widespread alveolar flooding in ARDS impairs alveolar ventilation, excludes oxygen, and inactivates surfactant; this, in turn, decreases lung compliance, increases dispersion of ventilation and perfusion, and produces intrapulmonary shunt. Intrapulmonary shunt is disclosed when hypoxemia does not improve despite oxygen administration; hypoxemia in ARDS does respond to positive end-expiratory pressure, which is applied carefully in accordance with strategies of lung-protective ventilation designed to avoid ventilator-associated lung injury and worsening ARDS. The acute respiratory distress syndrome (ARDS) is defined by noncardiogenic pulmonary edema and respiratory failure in the seriously ill patient. The diagnosis is clinical, established by the development of new bilateral pulmonary infiltrates and severe hypoxemia without congestive heart failure (1). The risk for ARDS also depends on both host and etiologic factors. The most common causes are sepsis, pneumonia, aspiration, trauma, pancreatitis, several blood transfusions, smoke or toxic gas inhalation, and certain types of drug toxicity (2, 3). Several etiologic factors often are present, and this increases the probability of developing the syndrome. The acute respiratory distress syndrome is a major cause of morbidity, death, and cost in intensive care units. Our review describes the clinical, etiologic, and physiologic basis of ARDS and summarizes our understanding of how its molecular pathogenesis leads to the physiologic alterations of respiratory failure, emphasizing factors known to be involved in the formation and resolution of permeability pulmonary edema. It also provides a physiologic basis for understanding and implementing modern strategies for the respiratory management of patients with ARDS. In 1967, Ashbaugh and colleagues (4) defined ARDS as an acute lung injury syndrome associated with trauma, sepsis, or aspiration. The syndrome's similarities to shock lung and neonatal respiratory distress led to its original name, the adult respiratory distress syndrome, now the acute respiratory distress syndrome. Over the years, ARDS became associated with clinical risk factors that may cause lung injury either by direct involvement or by secondary processes that activate systemic inflammation and coincidentally damage the lung. The incidence of ARDS in at-risk populations is not certain, but prospective estimates range from 1.5 to 12.9 cases per 100 000 people per year depending on diagnostic criteria (5). The most common cause of ARDS, severe infection, accounts for approximately half of cases. These infections may involve localized disease (such as pneumonia) or systemic disease, including sepsis, sepsis syndrome, and septic shock. Sepsis-related conditions, particularly severe gram-negative infections, are also associated with multiple organ failure with or without progressive respiratory failure. The multiple organ failure syndrome is the major cause of death in ARDS, and the mortality rate of the syndrome with ARDS is about 40% (6-9). The AmericanEuropean Consensus Conference on ARDS formally defined ARDS (see Clinical Principles) to improve diagnostic consistency and interpretation of epidemiologic and therapeutic studies (1). The AmericanEuropean Consensus Conference also recommended a working definition for milder acute lung injury also based on the presence of hypoxemia and pulmonary infiltrates without elevated left atrial pressure. Usually, the compliance of the lungs also decreases. The acute respiratory distress syndrome is distinguished solely by pulmonary gas exchange defined by the ratio of Pao 2 to the inspired fraction of oxygen (Fio 2). A Pao 2Fio 2 ratio of 300 or less defines acute lung injury, and a ratio of 200 or less defines ARDS regardless of the amount of positive end-expiratory pressure (PEEP) needed to support oxygenation. Physiologic indexes of oxygenation are diagnostically useful, but the Pao 2Fio 2 ratio and physiologic scoring systems do not correlate with prognosis (9, 10). The consensus definitions recognize the clinical syndromes without attention to specific molecular, immune, or physical events that cause respiratory failure. The acute respiratory distress syndrome is thus the clinical expression of a group of diverse processes that produce widespread alveolar damage. Regardless of cause, lung damage causes fluid to leak across the alveolarcapillary barrier (despite relatively normal pulmonary circulatory pressures) and to produce enough alveolar edema to cause the cardinal physiologic manifestation of the syndrome, refractory hypoxemia (Figure 1). Figure 1. Relationships between extravascular lung water and development of hypoxemia in the acute respiratory distress syndrome. o PAP ClinicalPathologic Correlation in ARDS The lung's alveolarcapillary structure normally provides a large surface for gas exchange and a tight barrier between alveolar gas and pulmonary capillary blood. Diffuse damage to the alveolar region occurs in the acute or exudative phase of acute lung injury and ARDS (Figure 2). This damage involves both the endothelial and epithelial surfaces and disrupts the lung's barrier function, flooding alveolar spaces with fluid, inactivating surfactant, causing inflammation, and producing severe gas exchange abnormalities and loss of lung compliance. These events are reflected in the presence of bilateral infiltrates, which are indistinguishable by conventional radiology from cardiogenic pulmonary edema (11). Computed tomography of the chest often demonstrates heterogeneous areas of consolidation and atelectasis, predominantly in the dependent lung (12, 13), although areas of apparent sparing may still show inflammation. Pathologic findings consist of diffuse alveolar damage, including capillary injury, and areas of exposed alveolar epithelial basement membrane (14-16). The alveolar spaces are lined with hyaline membranes and are filled with protein-rich edema fluid and inflammatory cells. The interstitial spaces, alveolar ducts, small vessels, and capillaries also contain macrophages, neutrophils, and erythrocytes. Figure 2. Cellular and molecular events that interfere with gas exchange in the acute respiratory distress syndrome. The acute phase may resolve or progress to a fibrosis phase with persistent hypoxemia, increased dead space, pulmonary hypertension, and further loss of lung compliance. Chest radiographs may show new linear opacities consistent with evolving fibrosis. Computed tomography often shows diffuse interstitial thickening and blebs or honeycombing (13). Pathologic examination of the lung shows fibrosis with collagen deposition, acute and chronic inflammation, and incomplete resolution of edema (16). The recovery phase of ARDS is characterized by resolution of hypoxemia and improvement in dead space and lung compliance. Radiographic abnormalities usually resolve, but microscopic fibrosis remains. Clinically, failure to improve in the first week of treatment and the presence of extensive alveolar epithelial injury are poor prognostic signs (3, 10, 17). Survivors of ARDS tend to be young, and pulmonary function generally recovers gradually over a year, but residual abnormalities often remain (18-24), including mild restriction or obstruction, low diffusing capacity, and impaired gas exchange with exercise (18-21). Persistent abnormalities of pulmonary function occur more commonly after severe ARDS and a need for prolonged mechanical ventilation (20, 21). Survivors of ARDS also have diminished health-related and pulmonary diseasespecific quality of life, as well as systemic effects, such as muscle wasting, weakness, and fatigue (22-24). Causes of ARDS In North America and Europe, sepsis (including pneumonia) is the most common cause of ARDS, but multiple transfusions, severe trauma, and aspiration of gastric contents are also independent risk factors (1-3, 5). Patients with sepsis are at the highest risk, and many patients with severe sepsis develop respiratory failure (25). Many infectious organisms, as well as molecular components of gram-negative and gram-positive bacteria, can trigger intense pulmonary inflammation. The presence and duration of septic shock, particularly if circulating endotoxin (lipopolysaccharide) is present, are associated with a higher incidence of ARDS (1). However, many patients with sepsis never develop ARDS, and many patients with sepsis-induced ARDS survive. In all causes of ARDS, innate genetic differences regulate the lung's immune responses and are important in pathogenesis. Innate immunity provides the first-line host defense against pathogens and may play a key role in the development of ARDS in both infections and other conditions. The innate immune system identifies certain patterns of cell activation; therefore, a few pattern recognition receptors recognize a wide range of microbes and endogenous ligands (such as fibronectin and hyaluronic acid) (26, 27). For instance, pattern recognition receptors recognize the highly conserved lipid A portion of lipopolysaccharide, which produces a pathogen-associated molecular pattern. Some patte