Since World War I, it has been recognized that some patients with nonthoracic injuries, severe pancreatitis, massive transfusion, sepsis, and other conditions develop respiratory distress, diffuse lung infiltrates, and respiratory failure, sometimes after a delay of hours to days. Ashbaugh et al described 12 such patients in 1967, using the term “adult respiratory distress syndrome” to describe this condition. 
Before research into the pathogenesis and treatment of this syndrome could proceed, it was necessary to formulate a clear definition of the syndrome. Such a definition was developed in 1994 by the American-European Consensus Conference (AECC) on acute respiratory distress syndrome (ARDS).  The term “acute respiratory distress syndrome” was used instead of “adult respiratory distress syndrome” because the syndrome occurs in both adults and children.
ARDS was recognized as the most severe form of acute lung injury (ALI), a form of diffuse alveolar injury. The AECC defined ARDS as an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence for cardiogenic pulmonary edema. The severity of hypoxemia necessary to make the diagnosis of ARDS was defined by the ratio of the partial pressure of oxygen in the patient’s arterial blood (PaO2) to the fraction of oxygen in the inspired air (FiO2). ARDS was defined by a PaO2/FiO2 ratio of less than 200, and in ALI, less than 300.
This definition was further refined in 2011 by a panel of experts and is termed the Berlin definition of ARDS.  ARDS is defined by timing (within 1 wk of clinical insult or onset of respiratory symptoms); radiographic changes (bilateral opacities not fully explained by effusions, consolidation, or atelectasis); origin of edema (not fully explained by cardiac failure or fluid overload); and severity based on the PaO2/FiO2 ratio on 5 cm of continuous positive airway pressure (CPAP). The 3 categories are mild (PaO2/FiO2 200-300), moderate (PaO2/FiO2 100-200), and severe (PaO2/FiO2 ≤100).
ARDS is associated with diffuse alveolar damage (DAD) and lung capillary endothelial injury. The early phase is described as being exudative, whereas the later phase is fibroproliferative in character.
Early ARDS is characterized by an increase in the permeability of the alveolar-capillary barrier, leading to an influx of fluid into the alveoli. The alveolar-capillary barrier is formed by the microvascular endothelium and the epithelial lining of the alveoli. Hence, a variety of insults resulting in damage either to the vascular endothelium or to the alveolar epithelium could result in ARDS.
The main site of injury may be focused on either the vascular endothelium (eg, sepsis) or the alveolar epithelium (eg, aspiration of gastric contents). Injury to the endothelium results in increased capillary permeability and the influx of protein-rich fluid into the alveolar space.
Injury to the alveolar lining cells also promotes pulmonary edema formation. Two types of alveolar epithelial cells exist. Type I cells, which make up 90% of the alveolar epithelium, are injured easily. Damage to type I cells allows both increased entry of fluid into the alveoli and decreased clearance of fluid from the alveolar space.
Type II alveolar epithelial cells are relatively more resistant to injury. However, type II cells have several important functions, including the production of surfactant, ion transport, and proliferation and differentiation into type l cells after cellular injury. Damage to type II cells results in decreased production of surfactant with resultant decreased compliance and alveolar collapse. Interference with the normal repair processes in the lung may lead to the development of fibrosis.
Neutrophils are thought to play a key role in the pathogenesis of ARDS, as suggested by studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS. Despite the apparent importance of neutrophils in this syndrome, ARDS may develop in profoundly neutropenic patients, and infusion of granulocyte colony-stimulating factor (G-CSF) in patients with ventilator-associated pneumonia (VAP) does not promote its development. This and other evidence suggests that the neutrophils observed in ARDS may be reactive rather than causative.
Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor, and numerous others), along with platelet sequestration and activation, are also important in the development of ARDS. An imbalance of proinflammatory and anti-inflammatory cytokines is thought to occur after an inciting event, such as sepsis. Evidence from animal studies suggests that the development of ARDS may be promoted by the positive airway pressure delivered to the lung by mechanical ventilation. This is termed ventilator-associated lung injury (VALI).
ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, which are more compliant than affected alveoli, may become overdistended by the delivered tidal volume, resulting in barotrauma (pneumothorax and interstitial air). Alveoli already damaged by ARDS may experience further injury from the shear forces exerted by the cycle of collapse at end-expiration and reexpansion by positive pressure at the next inspiration (so-called volutrauma).
In addition to the mechanical effects on alveoli, these forces promote the secretion of proinflammatory cytokines with resultant worsening inflammation and pulmonary edema. The use of positive end-expiratory pressure (PEEP) to diminish alveolar collapse and the use of low tidal volumes and limited levels of inspiratory filling pressures appear to be beneficial in diminishing the observed VALI.
ARDS causes a marked increase in intrapulmonary shunting, leading to severe hypoxemia. Although a high FiO2 is required to maintain adequate tissue oxygenation and life, additional measures, like lung recruitment with PEEP, are often required. Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity. Generally, oxygen concentrations higher than 65% for prolonged periods (days) can result in DAD, hyaline membrane formation, and, eventually, fibrosis.
ARDS is uniformly associated with pulmonary hypertension. Pulmonary artery vasoconstriction likely contributes to ventilation-perfusion mismatch and is one of the mechanisms of hypoxemia in ARDS. Normalization of pulmonary artery pressures occurs as the syndrome resolves. The development of progressive pulmonary hypertension is associated with a poor prognosis.
The acute phase of ARDS usually resolves completely. Less commonly, residual pulmonary fibrosis occurs, in which the alveolar spaces are filled with mesenchymal cells and new blood vessels. This process seems to be facilitated by interleukin (IL)-1. Progression to fibrosis may be predicted early in the course by the finding of increased levels of procollagen peptide III (PCP-III) in the fluid obtained by BAL. This and the finding of fibrosis on biopsy correlate with an increased mortality rate.
Multiple risk factors exist for ARDS. Approximately 20% of patients with ARDS have no identified risk factor. ARDS risk factors include direct lung injury (most commonly, aspiration of gastric contents), systemic illnesses, and injuries. The most common risk factor for ARDS is sepsis.
Given the number of adult studies, major risk factors associated with the development of ARDS include the following:
Trauma, with or without pulmonary contusion
Fractures, particularly multiple fractures and long bone fractures
Postperfusion injury after cardiopulmonary bypass
General risk factors for ARDS have not been prospectively studied using the 1994 EACC criteria. However, several factors appear to increase the risk of ARDS after an inciting event, including advanced age, female sex (noted only in trauma cases), cigarette smoking,  and alcohol use. For any underlying cause, increasingly severe illness as predicted by a severity scoring system such as the Acute Physiology And Chronic Health Evaluation (APACHE) increases the risk of development of ARDS.
A study by Glavan et al examined the association between genetic variations in the FAS gene and ALI susceptibility. The study identified associations between four single nucleotide polymorphisms and increased ALI susceptibility.  Further studies are needed to examine the role of FAS in ALI.
The incidence of ARDS varies widely, partly because studies have used different definitions of the disease. Moreover, to determine an accurate estimate of its incidence, all cases of ARDS in a given population must be found and included. Although this may be problematic, recent data are available from the United States and international studies that may clarify the true incidence of this condition.
United States statistics
In the 1970s, when a National Institutes of Health (NIH) study of ARDS was being planned, the estimated annual frequency was 75 cases per 100,000 population. Subsequent studies, before the development of the AECC definitions, reported much lower figures. For example, a study from Utah showed an estimated incidence of 4.8-8.3 cases per 100,000 population.
Data obtained more recently by the NIH-sponsored ARDS Study Network suggest that the incidence of ARDS may actually be higher than the original estimate of 75 cases per 100,000 population. A prospective study using the 1994 AECC definition was performed in King County, Washington, from April 1999 through July 2000 and found that the age-adjusted incidence of ALI was 86.2 per 100,000 person-years.  Incidence increased with age, reaching 306 per 100,000 person-years for people in aged 75-84 years.
On the basis of these statistics, it is estimated that 190,600 cases exist in the United States annually and that these cases are associated with 74,500 deaths.
The first study to use the 1994 AECC definitions was performed in Scandinavia, which reported annual rates of 17.9 cases per 100,000 population for ALI and 13.5 cases per 100,000 population for ARDS. 
Age-related differences in incidence
ARDS may occur in people of any age. Its incidence increases with advancing age, ranging from 16 cases per 100,000 person-years in those aged 15-19 years to 306 cases per 100,000 person-years in those between the ages of 75 and 84 years. The age distribution reflects the incidence of the underlying causes.
Sex-related differences in incidence
For ARDS associated with sepsis and most other causes, no differences in the incidence between males and females appear to exist. However, in trauma patients only, the incidence of the disease may be slightly higher among females.
Until the 1990s, most studies reported a 40-70% mortality rate for ARDS. However, 2 reports in the 1990s, one from a large county hospital in Seattle and one from the United Kingdom, suggested much lower mortality rates, in the range of 30-40%. [8, 9] Possible explanations for the improved survival rates may be better understanding and treatment of sepsis, recent changes in the application of mechanical ventilation, and better overall supportive care of critically ill patients.
Note that most deaths in ARDS patients are attributable to sepsis (a poor prognostic factor) or multiorgan failure rather than to a primary pulmonary cause, although the recent success of mechanical ventilation using smaller tidal volumes may suggest a role of lung injury as a direct cause of death.
Mortality in ARDS increases with advancing age. The study performed in King County, Washington, found mortality rates of 24% in patients between ages 15 and 19 years and 60% in patients aged 85 years and older. The adverse effect of age may be related to underlying health status.
Indices of oxygenation and ventilation, including the PaO2/FiO2 ratio, do not predict the outcome or risk of death. The severity of hypoxemia at the time of diagnosis does not correlate well with survival rates. However, the failure of pulmonary function to improve in the first week of treatment is a poor prognostic factor.
Peripheral blood levels of decoy receptor 3 (DcR3), a soluble protein with immunomodulatory effects, independently predict 28-day mortality in ARDS patients. In a study comparing DcR3, soluble triggering receptor expressed on myeloid cells (sTREM)-1, TNF-alpha, and IL-6 in ARDS patients, plasma DcR3 levels were the only biomarker to distinguish survivors from nonsurvivors at all time points in week 1 of ARDS.  Nonsurvivors had higher DcR3 levels than survivors, regardless of APACHE II scores, and mortality was higher in patients with higher DcR3 levels.
Morbidity is considerable. Patients with ARDS are likely to have prolonged hospital courses, and they frequently develop nosocomial infections, especially ventilator-associated pneumonia (VAP). In addition, patients often have significant weight loss and muscle weakness, and functional impairment may persist for months after hospital discharge. 
Severe disease and prolonged duration of mechanical ventilation are predictors of persistent abnormalities in pulmonary function. Survivors of ARDS have significant functional impairment for years following recovery.
In a study of 109 survivors of ARDS, 12 patients died in the first year. In 83 evaluable survivors, spirometry and lung volumes were normal at 6 months, but diffusing capacity remained mildly diminished (72%) at 1 year.  ARDS survivors had abnormal 6-minute walking distances at 1 year, and only 49% had returned to work. Their health-related quality of life was significantly below normal. However, no patient remained oxygen dependent at 12 months. Radiographic abnormalities had also completely resolved.
A study of this same group of patients 5 years after recovery from ARDS (9 additional patients had died and 64 were evaluated) was recently published and demonstrated continued exercise impairment and decreased quality of life related to both physical and neuropsychological factors. 
A study examining health-related quality of life (HRQL) after ARDS determined that ARDS survivors had poorer overall HRQL than the general population at 6 months after recovery.  This included lower scores in mobility, energy, and social isolation.
What would you like to print?