Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome: Definition; clinical features; and diagnosisAuthorsJohn Hansen-Flaschen, MDMark D Siegel, MDSection EditorPolly E Parsons, MDDeputy EditorKevin C Wilson, MDLast literature review version 18.1: enero 2010 | This topic last updated: enero 29, 2010

INTRODUCTION — A distinct type of hypoxemic respiratory failure characterized by acute abnormality of both lungs was first recognized during the 1960s. Military clinicians working in surgical hospitals in Vietnam called it shock lung, while civilian clinicians referred to it as adult respiratory distress syndrome [1]. Subsequent recognition that individuals of any age could be afflicted led to the current term, acute respiratory distress syndrome (ARDS).

The definition, clinical features, and diagnosis of ARDS will be reviewed here. Other issues related to ARDS are discussed separately. (See "Acute respiratory distress syndrome: Epidemiology; pathophysiology; pathology; and etiology" and "Acute respiratory distress syndrome: Prognosis" and "Mechanical ventilation in acute respiratory distress syndrome" and"Supportive care and oxygenation in acute respiratory distress syndrome" and "Novel therapies for the acute respiratory distress syndrome".)

DEFINITIONS — For more than 20 years, progress in understanding the epidemiology and clinical features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) was hampered by the absence of uniform definitions for these diseases. In 1994, the American-European Consensus Conference on ARDS defined both ALI and ARDS [2,3]. These definitions have been widely adopted by clinicians and researchers.

ALI requires all four of the following features in patients who have a risk factor for ARDS and no history of chronic lung disease:

Acute onset Bilateral infiltrates (radiographically similar to pulmonary edema) No evidence of elevated left atrial pressure (the pulmonary capillary wedge

pressure is ≤18 mmHg if measured) A ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2)

of 201 to 300 mmHg

ARDS is the same, except the PaO2/FiO2 is ≤200 mmHg.

Thus, only the PaO2/FiO2 distinguishes ALI from ARDS. The PaO2 is measured in mmHg and the FiO2 is expressed as a decimal between 0.21 and 1.00. As an example, a patient who has a PaO2 of 60 mmHg while receiving 80 percent oxygen, has a PaO2/FiO2 of 60 mmHg/0.80, or 75 mmHg. The amount of positive end-expiratory pressure (PEEP) is not considered when calculating the PaO2/FiO2.

Determining the PaO2/FiO2 requires arterial blood gas (ABG) analysis. However, arterial blood can be difficult to obtain from some patients. For such patients, the ratio of oxyhemoglobin saturation measured by pulse oximetry (SpO2) to FiO2 is a

reasonable substitute, according to a retrospective study of ABG measurements performed in adults receiving mechanical ventilation [4]. The study found that a SpO2/FiO2 of 235 predicted a PaO2/FiO2 of 200 (the threshold for ARDS) with a sensitivity of 85 percent and a specificity of 85 percent, while a SpO2/FiO2 of 315 predicted a PaO2/FiO2 of 300 (the threshold for ALI) with a sensitivity of 91 percent and a specificity of 56 percent.

Clinicians should be aware that the values of PaO2/FiO2 that define ALI and ARDS are somewhat arbitrary, since PaO2/FiO2 has not been shown to correlate with the severity of the lung injury, the clinical course, or mortality [5,6]. The lack of correlation between PaO2/FIO2 and clinical outcomes is discussed elsewhere. (See "Acute respiratory distress syndrome: Prognosis", section on 'Predictors'.)

Other methods of determining the PaO2/FiO2 (eg, using standard amounts of PEEP and FiO2 when measuring PaO2) may ultimately be a more reliable approach to characterizing these patients [7].

CLINICAL FEATURES — Patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) follow a similar clinical course. Therefore, we refer to ALI and ARDS collectively as ALI/ARDS in this section.

Initial course — The initial features of ALI/ARDS are due to both the precipitant (eg, fever and hypotension in a patient with sepsis) and the respiratory dysfunction. The pulmonary abnormalities typically develop within 48 to 72 hours of the inciting event and rapidly worsen [8]. Clinical findings include dyspnea, tachypnea, and hypoxemia. High concentrations of supplemental oxygen are generally required. A dry cough and chest pain may also be present.

Physical examination usually reveals tachycardia, cyanosis, tachypnea, and diffuse rales. Mechanical ventilation is almost universally required. (See "Mechanical ventilation in acute respiratory distress syndrome".)

Arterial blood gases usually detect an acute respiratory alkalosis, hypoxemia, and an elevated alveolar-arterial oxygen gradient (calculator 1). The hypoxemia is generally due to physiological shunting (calculator 2) [9]. (See "Oxygenation and mechanisms of hypoxemia", section on 'Right-to-left shunt'.)

Other laboratory abnormalities are related to the underlying risk factors. These may include leukocytosis, disseminated intravascular coagulation (DIC), and lactic acidosis.

The initial chest radiograph typically has bilateral alveolar infiltrates (picture 1), while computed tomography (CT) reveals patchy abnormalities that are more dense in dependent lung zones (picture 2) [10-12]. The infiltrates do not have to be diffuse or severe in ALI/ARDS; bilateral infiltrates of any severity are sufficient [13]. The absence of pulmonary venous congestion, Kerley B lines, cardiomegaly, and pleural effusions helps distinguish ALI/ARDS from pulmonary edema.

Subsequent course — Most patients who survive the initial period described above exhibit better oxygenation over the next several days. This is accompanied by decreasing alveolar infiltrates on the chest radiograph. Less ventilatory support may be required and weaning may begin. (See "Weaning from mechanical ventilation: Readiness testing".)

In contrast, some patients have persistent interstitial infiltrates and remain ventilator-dependent. A period of organization and fibrosis may follow. This is

characterized by increasing airway pressures, progressive pulmonary hypertension, and development of honeycombing on chest radiographs. The clinical course may become dominated by persistent ventilator dependence and complications.

Complications — Patients with ALI/ARDS are at high risk for complications, particularly after the initial phase of their illness has resolved. Some complications are related to prolonged mechanical ventilation (eg, pulmonary barotrauma, nosocomial pneumonia), while others are related to critical illness and being in the ICU (eg, deep venous thrombosis, gastrointestinal bleeding due to stress ulceration, poor nutrition, side effects from medications, and catheter-related infections). (See "Supportive care and oxygenation in acute respiratory distress syndrome".)

Barotrauma — Patients with ALI/ARDS are predisposed to pulmonary barotrauma due to a combination of factors, including tissue breakdown and mechanical ventilation [14,15]. The overall incidence of pulmonary barotrauma in patients with ALI/ARDS appears to be approximately 13 percent, according to an observational study that used data from 718 patients with ALI/ARDS who were enrolled in the ARDSNet trial of low tidal volume ventilation [16]. The study found the risk of pulmonary barotrauma to be highest among patients who received high levels of positive end-expiratory pressure (PEEP). The mean airway pressure, plateau pressure, and driving pressure (the difference between the plateau pressure and the PEEP) did not predict pulmonary barotrauma.

Barotrauma is rarely a direct cause of death in patients with ALI/ARDS. However, it appears to be an important cause of morbidity and can contribute to death in patients with other risk factors for a poor outcome [17]. The pathogenesis, risk factors, prevention, clinical presentation, diagnosis, management, and prognosis of pulmonary barotrauma are discussed in detail separately. (See "Pulmonary barotrauma during mechanical ventilation".)

Sedation/paralysis — Most patients with ALI/ARDS require sedation to facilitate mechanical ventilation. Rarely, the most severe may require neuromuscular blocking agents. While these agents may be necessary, they are associated with numerous side effects. Examples include prolonged mental status depression and persistent neuromuscular weakness [3,18]. The latter is particularly prominent when neuromuscular blocking agents are used concomitantly with glucocorticoids.

The use of sedatives and neuromuscular blocking agents in critically ill patients is reviewed elsewhere. (See "Use of sedative medications in critically ill patients" and "Use of neuromuscular blocking medications in critically ill patients" and "Neuromuscular weakness related to critical illness".)

Nosocomial infection — Nosocomial pneumonia is an important cause of morbidity and mortality in patients who have ALI/ARDS [19-22]. (See "Acute respiratory distress syndrome: Prognosis", section on 'Mortality'.)

The incidence of nosocomial pneumonia among patients with ALI/ARDS is uncertain because similar symptoms, signs, and radiographic findings make it difficult to distinguish pneumonia from the underlying ALI/ARDS [19,23]. The difficulty identifying pneumonia in patients with ALI/ARDS was illustrated by an autopsy study that found pneumonia in 58 percent of patients with ALI/ARDS, although pneumonia was suspected ante mortem in only 20 percent [24]. Conversely, 20 percent of patients thought to have pneumonia did not have histologic evidence of pneumonia.

Although the precise incidence of nosocomial pneumonia among patients with ALI/ARDS is uncertain, there is evidence that nosocomial pneumonia is more common among patients who are mechanically ventilated because of ALI/ARDS than among patients who are mechanically ventilated for other reasons. In an observational study of 243 consecutive patients who required mechanical ventilation, patients with ALI/ARDS were significantly more likely to develop nosocomial pneumonia than patients without ALI/ARDS (55 versus 28 percent) [25]. A possible reason for these findings is that patients with ALI/ARDS required longer durations of mechanical ventilation.

The diagnosis, prevention, and management of nosocomial pneumonia are discussed separately. (See "Clinical presentation and diagnosis of ventilator-associated pneumonia" and "Risk factors and prevention of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults" and "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults".)

Other — Other potential complications that characterize the hospital course of ALI/ARDS include the following:

Deep venous thrombosis (see "Diagnosis of suspected deep vein thrombosis of the lower extremity").

Gastrointestinal bleeding due to stress ulceration (see "Stress ulcer prophylaxis in the intensive care unit").

Poor nutrition (see "Nutritional support in critically ill patients: An overview"). Catheter-related infections (see "Diagnosis of intravascular catheter-related

infections" and "Prevention of intravascular catheter-related infections" and "Treatment of intravascular catheter-related infections").

DIAGNOSIS — The diagnostic evaluations of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the same. Therefore, we refer to ALI and ARDS collectively as ALI/ARDS in this section.

General approach — ALI/ARDS is a diagnosis of exclusion. In other words, neither ALI nor ARDS should be diagnosed until other causes of acute bilateral infiltrates, severe hypoxemia, and respiratory distress have been excluded.

Cardiogenic pulmonary edema is one such disease that should always be excluded, since it is common and can be indistinguishable clinically. Once cardiogenic pulmonary edema has been excluded, other considerations include pneumonia, diffuse alveolar hemorrhage, idiopathic acute eosinophilic pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia (Hamman-Rich syndrome), and rapidly progressive cancer [26].

Excluding cardiogenic pulmonary edema — Several diagnostic tests are available to help the clinician distinguish ALI/ARDS from cardiogenic pulmonary edema. They include measurement of plasma brain natriuretic peptide (BNP) levels, echocardiography, and right heart catheterization.

Brain natriuretic peptide — A plasma BNP level below 100 pg/mL favors ALI/ARDS, but higher levels neither confirm heart failure nor exclude ALI/ARDS [27,28]. This derives from an observational study of patients with ALI/ARDS (n=33) or cardiogenic pulmonary edema (n=21) [27]. The study found that a plasma BNP level less than 100 pg/mL identified ALI/ARDS with a sensitivity, specificity, positive

predictive value, and negative predictive value of 27, 95, 90, and 44 percent, respectively.

Echocardiography — Many clinicians use transthoracic echocardiography as the next diagnostic step if cardiogenic pulmonary edema cannot be excluded by clinical evaluation and measurement of the plasma BNP level. Detection of severe aortic valve dysfunction, severe mitral valve dysfunction, or a severely reduced left ventricular ejection fraction favors cardiogenic pulmonary edema. However, cardiogenic pulmonary edema cannot be excluded on the basis of an echocardiogram, since diastolic dysfunction and volume overload due to acute renal failure may exist even if the left heart function appears normal.

Right heart catheterization — There is ample evidence that indicates that there is no value to routine right heart catheterization for either the diagnosis or management of ALI/ARDS [29,30]. However, pulmonary artery catheterization may be considered if cardiogenic pulmonary edema cannot be excluded on the basis of the clinical evaluation, plasma BNP measurement, and echocardiogram. (See "Evaluation of acute decompensated heart failure", section on 'Swan-Ganz catheter'.)

Excluding other causes of hypoxemic respiratory failure — Alternative causes of acute hypoxemic respiratory failure with bilateral infiltrates should be considered once pulmonary edema due to heart failure has been excluded. If such diseases cannot be excluded on the basis of the clinical context and accompanying symptoms and signs, additional diagnostic testing (eg, bronchoscopy) should be performed:

Pneumonia is characterized by cough, fever, and dyspnea. Aerobic bacteria, Legionella pneumophila, Pneumocystis jirovecii (previously called Pneumocystis carinii), respiratory viruses, or viral inclusion bodies can frequently be identified in sputum or bronchoalveolar lavage specimens. (See "Diagnostic approach to community-acquired pneumonia in adults" and"Clinical manifestations and diagnosis of Legionella infection" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients".)

Diffuse alveolar hemorrhage may be associated with a large, otherwise unexplained drop in the hemoglobin concentration and hematocrit. While hemoptysis may be minimal or absent, bronchoscopy often reveals frothy bloody secretions throughout the airways and invariably detects an increasing amount of red blood cells in serial bronchoalveolar lavage specimens. The recovery of hemosiderin-laden macrophages from bronchoalveolar lavage fluid is strongly suggestive of diffuse alveolar hemorrhage. (See "The diffuse alveolar hemorrhage syndromes".)

Idiopathic acute eosinophilic pneumonia (IAEP) occurs in previously healthy individuals and is characterized by cough, fever, dyspnea, and sometimes chest pain. Bronchoalveolar lavage specimens always contain a large number of eosinophils, typically 35 to 55 percent of all recovered cells [31,32]. Peripheral eosinophil may or may not be present [33]. (See"Idiopathic acute eosinophilic pneumonia".)

Cryptogenic organizing pneumonia (COP) often mimics community-acquired pneumonia with an onset that is heralded by a flu-like illness with fever, malaise,

fatigue, and cough. The most common features at presentation are a persistent nonproductive cough, dyspnea with exertion, and weight loss. Bronchoalveolar lavage usually contains a smaller proportion of macrophages and higher proportions of lymphocytes, neutrophils, and eosinophils than healthy patients. This "mixed pattern" of increased cellularity is thought to be characteristic of COP. The diagnosis is made by ruling out infectious causes of pneumonia and documenting typical pathologic changes in tissue obtained by open lung biopsy. (See "Cryptogenic organizing pneumonia".)

Cancer can disseminate through the lungs so rapidly that the ensuing respiratory failure may be mistaken for ALI/ARDS. This is most often due to lymphoma or acute leukemia, but lymphangitic spread of solid tumors occasionally behaves this way. Cytological preparation of bronchoscopic specimens (eg, brushings, lavage) may reveal malignant cells.

Miliary tuberculosis should be considered when ALI/ARDS develops in patients who are hospitalized because of a systemic febrile illness [34,35]. The diagnosis is made by recovery of acid-fast bacilli from bronchoalveolar lavage fluid. (See "Clinical manifestations; diagnosis; and treatment of miliary tuberculosis".)

Open lung biopsy is a reasonable consideration when alternative causes of acute hypoxemic respiratory failure cannot be excluded on the basis of the clinical context, symptoms, signs, and bronchoscopy [36,37]. The safety of biopsy in selected patients with hypoxemic respiratory failure was demonstrated in a retrospective study of 57 patients with ALI/ARDS (mean PaO2/FiO2 was 145 mmHg) who underwent open lung biopsy [36]. The rate of major complications was 7 percent, with no deaths attributed to the biopsy. Although the overall complication rate was 39 percent, most of which were minor and related to persistent air leaks. The results of the biopsy resulted in the addition of specific therapy in 60 percent of patients and withdrawal of unnecessary therapy in 37 percent.

Generally speaking, we believe that lung biopsy should be reserved for carefully selected patients whose acute respiratory failure remains of uncertain etiology after nondiagnostic bronchoscopy and in whom the following remain diagnostic possibilities: diffuse alveolar hemorrhage, COP, disseminated cancer, vasculitis, or an undiagnosed diffuse lung disease.

Final diagnosis — ALI/ARDS is diagnosed once cardiogenic pulmonary edema and the alternative causes of acute hypoxemic respiratory failure with bilateral infiltrates have been excluded, as described above.

The cause of the lung injury should be sought concomitantly with the diagnostic evaluation. The purpose of identifying the cause of the lung injury is to determine whether additional therapy is indicated and to prevent recurrent lung injury. The potential causes of ALI/ARDS are reviewed separately. (See "Acute respiratory distress syndrome: Epidemiology; pathophysiology; pathology; and etiology", section on 'Etiologies and predisposing factors'.)

When the cause of the ALI/ARDS cannot be identified despite a thorough search, the ALI/ARDS is considered idiopathic. Patients with idiopathic ALI/ARDS who had a lung biopsy that demonstrated organizing diffuse alveolar damage can be diagnosed as having acute interstitial pneumonia (Hamman-Rich syndrome). This is a rare and fulminant disease that most commonly occurs in previously healthy individuals [38,39]. It is described separately. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

SUMMARY AND RECOMMENDATIONS

Acute lung injury (ALI) is defined by the following features: acute onset, bilateral infiltrates, no evidence of elevated left atrial pressure, and an arterial oxygen tension to fraction of inspired oxygen ratio (PaO2/FiO2) of 201 to 300 mmHg. (See 'Definitions' above.)

Acute respiratory distress syndrome (ARDS) is similarly defined by the following features: acute onset, bilateral infiltrates, no evidence of elevated left atrial pressure, and a PaO2/FiO2 of ≤200 mmHg. (See 'Definitions' above.)

The initial courses of ALI and ARDS are characterized by pulmonary abnormalities that typically develop within 48 hours of the inciting event and rapidly worsen. These include dyspnea, tachypnea, and hypoxemia. Physical examination usually reveals tachycardia, cyanosis, tachypnea, and diffuse rales, while arterial blood gases usually detect an acute respiratory alkalosis, hypoxemia, and an elevated alveolar-arterial oxygen gradient. The initial chest radiograph typically has bilateral, fluffy alveolar infiltrates with prominent air bronchograms. Mechanical ventilation is almost universally required. (See 'Initial course' above.)

Following the initial period, most patients with ALI and ARDS exhibit better oxygenation and decreasing alveolar infiltrates on the chest radiograph. However, some have persistent interstitial infiltrates and ventilator-dependence. (See 'Subsequent course' above and 'Complications' above.)

ALI and ARDS are diagnoses of exclusion. Cardiogenic pulmonary edema and other causes of acute hypoxemic respiratory failure with bilateral infiltrates (eg, pneumonia, diffuse alveolar hemorrhage) must be excluded before the diagnosis of ALI or ARDS is made. (See 'Diagnosis' above.)

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GRAPHICS

Acute respiratory distress syndrome

Chest x-ray showing diffuse, bilateral, alveolar infiltrates without cardiomegaly in a patient with ARDS.

Courtesy of Steven E Weinberger, MD.

ARDS CT

ARDS due to sepsis after pneumococcal pneumonia.

Acute respiratory distress syndrome: Epidemiology; pathophysiology; pathology; and etiologyAuthorMark D Siegel, MDSection EditorPolly E Parsons, MDDeputy EditorKevin C Wilson, MDLast literature review version 18.1: enero 2010 | This topic last updated: enero 29, 2010

INTRODUCTION — A distinct type of hypoxemic respiratory failure characterized by acute abnormality of both lungs was first recognized during the 1960s. Military clinicians working in surgical hospitals in Vietnam called it shock lung, while civilian clinicians referred to it as adult respiratory distress syndrome [1]. Subsequent recognition that individuals of any age could be afflicted led to the current term, acute respiratory distress syndrome (ARDS).

The epidemiology, pathophysiology, pathologic stages, and etiologies of ARDS will be reviewed here. Other issues related to ARDS are discussed separately. (See "Acute respiratory distress syndrome: Definition; clinical features; and diagnosis" and "Acute respiratory distress syndrome: Prognosis" and "Mechanical ventilation in acute respiratory distress syndrome" and "Supportive care and oxygenation in acute respiratory distress syndrome" and "Novel therapies for the acute respiratory distress syndrome".)

DEFINITIONS — Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are both defined by the acute onset of bilateral infiltrates consistent with

pulmonary edema, but without evidence of elevated left atrial pressure. The pulmonary capillary wedge pressure is ≤18 mmHg if measured.

The degree of hypoxemia differentiates ALI and ARDS. Patients with ALI have a ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) of 201 to 300 mmHg. In contrast, patients with ARDS have worse hypoxemia, with a PaO2/FiO2 of ≤200 mmHg. The amount of positive end-expiratory pressure (PEEP) is not accounted for when determining whether a patient has ALI or ARDS.

The definitions of ALI and ARDS are discussed in more detail elsewhere. (See "Acute respiratory distress syndrome: Definition; clinical features; and diagnosis", section on 'Definitions'.)

EPIDEMIOLOGY — The incidence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) were determined in a multicenter, population-based, prospective cohort study in the United States [2]. The studied followed 1113 patients with ALI or ARDS for 15 months beginning in 1999 or 2000:

The age-adjusted incidence was 86 per 100,000 person-years for ALI and 64 per 100,000 person-years for ARDS.

The incidence increased with patient age from 16 per 100,000 person-years among individuals 15 to 19 years of age to 306 per 100,000 person-years among individuals 75 to 84 years of age.

Extrapolation of the data suggested that there are approximately 190,000 cases of ALI in the United States each year [2].

Within intensive care units, approximately 10 to 15 percent of admitted patients and up to 20 percent of mechanically ventilated patients meet criteria for ALI or ARDS [3-6]. The incidence of ALI may be somewhat higher in the United States than in other countries [7].

PATHOPHYSIOLOGY — Healthy lungs regulate the movement of fluid to maintain a small amount of interstitial fluid and dry alveoli. This is interrupted by lung injury, causing excess fluid in both the interstitium and alveoli. Consequences include impaired gas exchange, decreased compliance, and increased pulmonary arterial pressure.

Baseline — Normal lung function requires that dry, patent alveoli be closely situated to appropriately perfused capillaries (picture 1) [8]. The normal pulmonary capillary endothelium is selectively permeable: fluid crosses the membranes under the control of hydrostatic and oncotic forces, while serum proteins remain intravascular.

The Starling equation describes the forces that direct fluid movement between the vessels and the interstitium [9]. A simplified version of the equation is:

  Q = K x [(Pmv - Ppmv) - rc (πmv - πpmv)]

where Q represents the net transvascular flow of fluid, K the permeability of the endothelial membrane, Pmv the hydrostatic pressure within the lumen of the microvessels, Ppmv the hydrostatic pressure in the perimicrovascular space, rc represents the reflection coefficient of the capillary barrier, πmv the oncotic pressure in the circulation, and πpmv the oncotic pressure in the perimicrovascular compartment. (See "Pathophysiology and etiology of edema in adults".)

The balance of hydrostatic and oncotic forces normally allows small quantities of fluid into the interstitium, but three mechanisms prevent alveolar edema (algorithm 1A-D) [9]:

Retained intravascular protein maintains an oncotic gradient favoring reabsorption

The interstitial lymphatics can return large quantities of fluid to the circulation

Tight junctions between alveolar epithelial cells prevent leakage into the air spaces

Injury — Acute lung injury and acute respiratory distress syndrome (collectively referred to as ALI/ARDS) are consequences of an alveolar injury producing diffuse alveolar damage (figure 1 and figure 2) [10]. The injury causes release of pro-inflammatory cytokines such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-8 [11-16]. These cytokines recruit neutrophils to the lungs, where they become activated and release toxic mediators (eg, reactive oxygen species and proteases) that damage the capillary endothelium and alveolar epithelium [10,17-21].

Damage to the capillary endothelium and alveolar epithelium allows protein to escape from the vascular space. The oncotic gradient that favors resorption of fluid is lost and fluid pours into the interstitium, overwhelming the lymphatics [22]. The ability to upregulate alveolar fluid clearance may also be lost [23]. The result is that the air spaces fill with bloody, proteinaceous edema fluid and debris from degenerating cells. In addition, functional surfactant is lost, resulting in alveolar collapse.

Consequences — Lung injury has numerous consequences including impairment of gas exchange, decreased lung compliance, and increased pulmonary arterial pressure.

Impaired gas exchange — Impaired gas exchange in ALI/ARDS is primarily due to ventilation-perfusion mismatching: physiologic shunting causes hypoxemia, while increased physiologic dead space impairs carbon dioxide elimination [24,25]. A high minute volume is generally needed to maintain a normal arterial carbon dioxide tension (PaCO2), although hypercapnia is uncommon. (See "Oxygenation and mechanisms of hypoxemia".)

Decreased lung compliance — Decreased pulmonary compliance is one of the hallmarks of ALI/ARDS [26]. It is a consequence of the stiffness of poorly or nonaerated lung, rather than the pressure-volume characteristics of residual functioning lung units [27]. Even small tidal volumes can exceed the lung's inspiratory capacity and cause a dramatic rise in airway pressures [26].

Pulmonary hypertension — Pulmonary hypertension (PH) occurs in up to 25 percent of patients with ALI/ARDS who undergo mechanical ventilation [28-30]. Causes include hypoxic vasoconstriction, vascular compression by positive airway pressure, parenchymal destruction, airway collapse, hypercarbia, and pulmonary vasoconstrictors [31]. The clinical importance of PH in most patients with ALI/ARDS is uncertain. PH severe enough to cor pulmonale is rare, but it is associated with an increased risk of death [32,33].

Increased airways resistance (Raw) is also a feature of ARDS, although its clinical significance is uncertain [34,35].

PATHOLOGIC STAGES — Patients with acute respiratory distress syndrome (ARDS) tend to progress through three relatively discrete pathologic stages (graph 1) [36]. The initial stage is the exudative stage, characterized by diffuse alveolar damage. After approximately seven to ten days, a proliferative stage develops, characterized by resolution of pulmonary edema, proliferation of type II alveolar cells, squamous metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen. Some patients progress to a fibrotic stage, characterized by obliteration of normal lung architecture, diffuse fibrosis, and cyst formation.

ETIOLOGIES AND PREDISPOSING FACTORS — Acute lung injury and acute respiratory distress syndrome are collectively referred to as ALI/ARDS. ALI/ARDS has traditionally been conceptualized as a pattern of lung injury and clinical manifestations that can be caused by a variety of insults. However, the validity of the assumption that different inciting events cause a similar pattern of lung injury and similar clinical features has been questioned because numerous studies have found more severe reductions in lung compliance and less responsiveness to positive end-expiratory pressure (PEEP) when the ALI/ARDS was due to a pulmonary process than when it was due to an extrapulmonary precipitant, such as sepsis [37-40].

More than 60 possible causes of ALI/ARDS have been identified and other potential causes continue to emerge as adverse pulmonary reactions to new therapies are observed (table 1). However, only a few common causes account for most cases of ALI/ARDS [6,41-43]. Factors that may predispose a patient to develop ALI/ARDS, but probably can't cause ALI/ARDS, have also been identified.

Sepsis — Sepsis is the most common cause of ALI/ARDS [41,42,44,45]. It should be the first etiology considered whenever ALI/ARDS develops in a patient who is predisposed to serious infection or in association with a new fever or hypotension. (See "Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis".)

The risk of developing ALI/ARDS may be particularly high among septic patients with a history of alcoholism [46-48]. This was illustrated by a prospective cohort study that determined the incidence of ALI/ARDS in 220 patients with septic shock [47]. The incidence of ALI/ARDS among patients who chronically abuse alcohol was 70 percent, compared to 31 percent among patients who did not chronically abuse alcohol. A possible explanation for these findings is that alcoholism may decrease the concentration of glutathione in the epithelial lining fluid, predisposing the lung to oxidative injury [46,49,50]. Alternatively, chronic alcohol abuse may increase the risk of ALI/ARDS by enhancing inappropriate leukocyte adhesion to endothelial cells [51].

Aspiration — Observational evidence indicates that ALI/ARDS will develop in approximately one-third of hospitalized patients who have a recognized episode of aspiration of gastric contents [41,43,52].

It was initially suggested that aspirated contents had to have a pH less than 2.5 to cause severe lung injury [53], however more recent animal studies have shown that aspiration of non-acidic gastric contents can also cause widespread damage to the lungs [54]. This suggests that gastric enzymes and small food particles also contribute to the lung injury.

The unexpected development of ALI/ARDS may be the only indication that an intubated patient has developed a tracheoesophageal fistula. This is a rare complication of intubation.

Pneumonia — Community acquired pneumonia is probably the most common cause of ALI/ARDS that develops outside of the hospital [55]. Common pathogens include Streptococcus pneumoniae [56], Legionella pneumophila, Pneumocystis jirovecii (formerly called Pneumocystis carinii), Staphylococcus aureus, enteric gram negative organisms, and a variety of respiratory viruses [57,58]. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" and "Diagnostic approach to community-acquired pneumonia in adults".)

Nosocomial pneumonias can also progress to ALI/ARDS. Staphylococcus aureus, Pseudomonas aeruginosa, and other enteric gram negative bacteria are the most commonly implicated pathogens. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults".)

Severe trauma — ALI/ARDS is a complication of severe trauma. There are several situations during which ALI/ARDS seems to be particularly common following trauma [59]:

Bilateral lung contusion following blunt trauma [60]. Fat embolism after long bone fractures. In this situation, ALI/ARDS typically

appears 12 to 48 hours after the trauma. This complication has decreased since immobilization for transport to the hospital became routine [61]. (See "Fat embolism syndrome".)

Sepsis may be the most common cause of ALI/ARDS that develops several days or more after severe trauma or burns.

Massive traumatic tissue injury may directly precipitate or predispose a patient to ALI/ARDS [59,62].

Although ALI/ARDS can contribute to the length of critical illness following severe trauma, it does not appear to independently increase the risk of death [63]. Trauma-related ALI/ARDS has a significantly better prognosis than ALI/ARDS that is not related to trauma [64].

Massive transfusion — Transfusion of more than 15 units of red blood cells is a risk factor for the development of ALI/ARDS [42]. It is unknown whether the transfusion injures the lungs or the need for massive transfusion identifies patients who are at high risk for ALI/ARDS from other causes [65]. Transfusion of smaller volumes of packed red blood cells may also increase the risk of developing ALI/ARDS, as well as increasing the risk of mortality among patients with established ALI/ARDS [66]. (See "Massive blood transfusion".)

Transfusion-related acute lung injury — Transfusion of even one unit of a plasma-containing blood product sometimes causes ALI/ARDS [67,68]. Fresh frozen plasma, platelet, and packed red blood cell transfusions have all been implicated. By definition, respiratory distress becomes apparent within six hours of completion of the transfusion. The mechanism in incompletely understood and may be multifactorial. (See "Transfusion-related acute lung injury (pulmonary leukoagglutinin reactions)".)

Lung and hematopoietic stem cell transplantation — During the first two or three days after surgery, lung transplant recipients are prone to primary graft failure. This devastating form of ALI/ARDS is attributed to imperfect preservation of the transplanted lung. (See "Primary lung graft dysfunction".)

Hematopoietic stem cell transplant patients are at risk for ALI/ARDS due to a variety of infectious and noninfectious causes. Noninfectious insults include idiopathic pneumonia syndrome, engraftment syndrome, and diffuse alveolar hemorrhage [69]. The lung injury appears to be partly related to the inflammation associated with chemoradiation conditioning regimens, as well as T cell alloreactivity. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation" and "Pulmonary complications after autologous hematopoietic cell transplantation".)

Drugs and alcohol — ALI/ARDS can occur following an overdose. Drugs that have been implicated include aspirin, cocaine, opioids, phenothiazines, and tricyclic antidepressants [70,71]. Idiosyncratic reactions to other drugs (eg, protamine, nitrofurantoin), including certain chemotherapeutic agents, occasionally precipitate ALI/ARDS after therapeutic doses. Radiologic contrast media can also provoke ALI/ARDS in susceptible individuals [72]. Alcohol abuse increases the risk of ALI/ARDS due to other causes (eg, sepsis, trauma), but does not cause ALI/ARDS [73].

Genetic determinants — It seems likely that there are genetic determinants that increase an individual's risk of developing ALI/ARDS, since only a small proportion of the patients who are exposed to typical insults actually develop ALI/ARDS [74]. Studies that link mutations in the surfactant protein B (SP-B) gene to an increased risk of ALI/ARDS support this notion [75,76]. Insertion-deletion polymorphisms associated with the angiotensin converting enzyme (ACE) gene have also been suggested as a possible risk factor for ALI/ARDS [77], although not all studies support this observation [78].

Other — Other possible risk factors for ALI/ARDS include cigarette smoking [79], cardiopulmonary bypass [80,81], pneumonectomy [82], acute pancreatitis [83], and near drowning [52,84,85]. (See "Submersion injuries (near-drowning)".)

Venous air embolism can occasionally cause ALI/ARDS. Outside of the operating room, the most common portal of entry for the air is a central venous catheter left open to the air [86]. (See "Air embolism".)

SUMMARY AND RECOMMENDATIONS

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are both defined by the acute onset of bilateral infiltrates consistent with pulmonary edema, but without evidence of elevated left atrial pressure. The severity of the hypoxemia distinguishes ARDS from ALI. (See 'Definitions' above.)

Healthy lungs regulate the movement of fluid to maintain a small amount of interstitial fluid and dry alveoli. In patients with ALI or ARDS, this regulation is interrupted by lung injury, causing excess fluid in both the interstitium and alveoli. Consequences include impaired gas exchange, decreased compliance, and increased pulmonary arterial pressure.(See'Pathophysiology' above.)

Patients with ARDS tend to progress through three relatively discrete pathologic stages: the exudative stage, proliferative stage, and fibrotic stage. (See 'Pathologic stages' above.)

More than 60 possible causes of ALI and ARDS have been identified and other potential causes continue to emerge as adverse pulmonary reactions to new therapies are observed. However, only a few common causes account for most cases of ALI or ARDS. Factors that may predispose a patient to develop ALI or ARDS have also been identified. (See 'Etiologies and predisposing factors' above.)

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GRAPHICS

Normal lung

High power photomicrograph shows alveoli containing capillaries within a narrow interstitium. The alveoli are lined with thin, elongated type I pneumoctes (red arrow) and smaller numbers of cuboidal type II pneumocytes (green arrow).

Courtesy of Steven E Weinberger, MD.

Protective mechanisms against pulmonary edema

An osmotic gradient favoring fluid reabsorption from the interstitium is maintained by retention of serum proteins within the intravascular space. Fluid which does leak into the interstitium is transported to lymphatics from which it is returned to the circulation. Finally, tight junctions between alveolar epithelial cells prevent leakage of fluid into the alveolar space. Arrows represent lymphatic movement; small circles represent protein.

Early development of interstitial edema

Breakdown of the capillary endothelial barrier allows leakage of serum proteins into the interstitial space, undoing the osmotic gradient which normally promotes fluid reabsorption. Arrows represent lymphatic movement; small circles represent protein.

Development of interstitial edema

The quantity of fluid pouring from the capillaries overwhelms the capacity of the interstitium and the lymphatics, resulting in interstitial edema. Arrows represent lymphatic movement; small circles represent protein.

Development of alveolar edema

Breakdown of the alveolar epithelial barrier allows leakage of edema fluid into the alveolar space. Arrows represent lymphatic movement; small circles represent protein.

Diffuse alveolar damage

Photomicrograph shows early diffuse alveolar damage with minimal alveolar septal thickening, hyperplasia of pneumocytes, and eosinophilic hyaline membranes (arrow).

Courtesy of Jeffrey L Myers, MD.

Normal lung

High power photomicrograph shows alveoli containing capillaries within a narrow interstitium. The alveoli are lined with thin, elongated type I pneumoctes (red arrow) and smaller numbers of cuboidal type II pneumocytes (green arrow).

Courtesy of Steven E Weinberger, MD.

Diffuse alveolar damage

High power photomicrograph shows changes typical of the proliferative or late stage of diffuse alveolar damage. Although hyaline membranes are still identifiable, the histologic picture is now dominated by thickening and reorganization of interstitial structures due mainly to marked proliferation of mesenchymal spindle cells, including both fibroblasts and myofibroblasts.

Courtesy of Jeffrey L Myers, MD.

Normal lung

High power photomicrograph shows alveoli containing capillaries within a narrow interstitium. The alveoli are lined with thin, elongated type I pneumoctes (red arrow) and smaller numbers of cuboidal type II pneumocytes (green arrow).

Courtesy of Steven E Weinberger, MD.

Time course of ARDS

Schematic representation of the time course of the acute respiratory distress syndrome (ARDS). During the early (or exudative) phase, the lesion is characterized by high permeability pulmonary edema followed by the formation of hyaline membranes. After seven to ten days, a proliferative phase may develop, with marked interstitial inflammation, fibrosis, and disordered healing.

Redrawn from Katzenstein AA, Askin FB. Surgical Pathology of Non-neoplastic Lung Disease. Saunders, Philadelphia, 1982.

Abbreviated list of conditions associated with ARDSSepsis

Aspiration

Infectious pneumonia

Severe trauma

Surface burns

Multiple blood transfusions

Leukoagglutin reactions

Pancreatitis

Drug overdose

Near drowning

Smoke inhalation

Cardiopulmonary bypass

Pulmonary contusion

Multiple fractures

Following upper airway obstruction

Following bone marrow transplantation

Drug reaction

Venous air embolism

Amniotic fluid embolism

Neurogenic pulmonary edema

Acute eosinophilic pneumonia*

Bronchiolitis obliterans organizing pneumonia (BOOP)*

Miliary tuberculosis*

* Specific treatment required.