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BACKGROUND 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.[1] 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).[2] 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. According to the AECC criteria, the severity of hypoxemia necessary to make the diagnosis of ARDS is defined by the ratio of the partial pressure of oxygen in the patients arterial blood (PaO2) to the fraction of oxygen in the inspired air (FIO2). In ARDS, the PaO2/FIO2 ratio is less than 200, and in ALI, it is less than 300. In addition, cardiogenic pulmonary edema must be excluded either by clinical criteria or by a pulmonary capillary wedge pressure (PCWP) lower than 18 mm Hg in patients with a pulmonary artery (Swan-Ganz) catheter in place. PATHOPHYSIOLOGY 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 (socalled 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. ETIOLOGY 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:

Bacteremia Sepsis Trauma, with or without pulmonary contusion Fractures, particularly multiple fractures and long bone fractures Burns Massive transfusion Pneumonia Aspiration Drug overdose Near drowning Postperfusion injury after cardiopulmonary bypass Pancreatitis Fat embolism 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,[3] 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.

Genetic factors
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.[4] Further studies are needed to examine the role of FAS in ALI. EPIDEMIOLOGY 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 ageadjusted incidence of ALI was 86.2 per 100,000 person-years.[5] 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.

International statistics

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.[6]

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. PROGNOSIS 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%.[7, 8] 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.[9] 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.[10] 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.[10] 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.[11] 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.[12] This included lower scores in mobility, energy, and social isolation. HISTORY Acute respiratory distress syndrome (ARDS) is characterized by the development of acute dyspnea and hypoxemia within hours to days of an inciting event, such as trauma, sepsis, drug overdose, massive transfusion, acute pancreatitis, or aspiration. In many cases, the inciting event is obvious, but, in others (eg, drug overdose), it may be harder to identify. Patients developing ARDS are critically ill, often with multisystem organ failure, and they may not be capable of providing historical information. Typically, the illness develops within 12-48 hours after the inciting event, although, in rare instances, it may take up to a few days. With the onset of lung injury, patients initially note dyspnea with exertion. This rapidly progresses to severe dyspnea at rest, tachypnea, anxiety, agitation, and the need for increasingly high concentrations of inspired oxygen. PHYSICAL ASSESSMENT Physical findings often are nonspecific and include tachypnea, tachycardia, and the need for a high fraction of inspired oxygen (FIO2) to maintain oxygen saturation. The patient may be febrile or hypothermic. Because ARDS often occurs in the context of sepsis, associated hypotension and peripheral vasoconstriction with cold extremities may be present. Cyanosis of the lips and nail beds may occur. Examination of the lungs may reveal bilateral rales. Rales may not be present despite widespread involvement. Because the patient is often intubated and mechanically ventilated, decreased breath sounds over 1 lung may indicate a pneumothorax or endotracheal tube down the right main bronchus. Manifestations of the underlying cause (eg, acute abdominal findings in the case of ARDS caused by pancreatitis) are present. In a septic patient without an obvious source, pay careful attention during the physical examination to identify potential causes of sepsis, including signs of lung consolidation or findings consistent with an acute abdomen. Carefully examine sites of intravascular lines, surgical wounds, drain sites, and decubitus ulcers for evidence of infection. Check for subcutaneous air, a manifestation of infection or barotrauma. Because cardiogenic pulmonary edema must be distinguished from ARDS, carefully look for signs of congestive heart failure or intravascular volume overload, including jugular venous distention, cardiac murmurs and gallops, hepatomegaly, and edema.

COMPLICATIONS Patients with ARDS often require high-intensity mechanical ventilation, including high levels of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) and, possibly, high mean airway pressures; thus, barotrauma may occur. Patients present with pneumomediastinum, pneumothorax, or both. Other potential complications that may occur in these mechanically ventilated patients include accidental extubation and right mainstem intubation. If prolonged mechanical ventilation is needed, patients may eventually require tracheostomy. With prolonged intubation and tracheostomy, upper airway complications may occur, most notably postextubation laryngeal edema and subglottic stenosis. Because patients with ARDS often require prolonged mechanical ventilation and invasive hemodynamic monitoring, they are at risk for serious nosocomial infections, including ventilator-associated pneumonia (VAP) and line sepsis. The incidence of VAP in ARDS patients may be as high as 55% and appears to be higher than that in other populations requiring mechanical ventilation. Preventive strategies including elevation of head of the bed, use of subglottic suction endotracheal tubes, and oral decontamination. Other potential infections include urinary tract infection (UTI) related to the use of urinary catheters and sinusitis related to the use of nasal feeding and drainage tubes. Patients may also develop Clostridium difficile colitis as a complication of broad-spectrum antibiotic therapy. Patients with ARDS, because of the extended intensive care unit (ICU) stay and treatment with multiple antibiotics, may also develop infections with drug-resistant organisms such as methicillin-resistantStaphylococcus aureus (MRSA) and vancomycinresistant Enterococcus (VRE). In a study of survivors of ARDS, significant functional impairment was noted at 1 year, primarily related to muscle wasting and weakness.[10] Corticosteroid treatment and use of neuromuscular blockade are risk factors for muscle weakness and poor functional recovery. Patients may have difficulty weaning from mechanical ventilation. Strategies to facilitate weaning, such as daily interruption of sedation,[13] early institution of physical therapy, attention to maintaining nutrition, and use of weaning protocols, may decrease the duration of mechanical ventilation and facilitate recovery. Renal failure is a frequent complication of ARDS, particularly in the context of sepsis. Renal failure may be related to hypotension, nephrotoxic drugs, or underlying illness. Fluid management is complicated in this context, especially if the patient is oliguric. Multisystem organ failure, rather than respiratory failure alone, is usually the cause of death in ARDS. Other potential complications include ileus, stress gastritis, and anemia. Stress ulcer prophylaxis is indicated for these patients. Anemia may be prevented by the use of growth factors (epopoietin). SUMMARY SUMMARY AND RECOMMENDATIONS

Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by the acute onset of bilateral alveolar infiltrates and hypoxemia. Diagnostic criteria for ARDS are provided separately. (See "Acute respiratory distress syndrome: Clinical features and diagnosis", section on 'Diagnostic criteria'.)

The underlying cause of the ARDS is the usual cause of death among patients who die early. In contrast, sepsis due to nosocomial pulmonary infection is the most common cause of death among patients who die later in their clinical course. Patients seldom die from respiratory failure. (See 'Mortality' above.) There are numerous factors that can be assessed during the acute illness that may predict mortality. However, no single factor appears to be superior to the others. (See 'Predictors' above.) Studies suggest that survival has improved for patients with ARDS. Among long-term survivors, many have abnormalities in pulmonary function that are generally mild, as well as reduced quality of life for at least two years following the acute illness. There is growing recognition that survivors of ARDS struggle with physical, cognitive, and psychological disorders that may last for months or years following their acute illness.

MORTALITY ARDS is associated with appreciable mortality, with estimates ranging from 26 to 58 percent [4-10]. The underlying cause of the ARDS is the most common cause of death among patients who die early [7,8,11,12]. In contrast, nosocomial pneumonia and sepsis are the most common causes of death among patients who die later in their clinical course [11]. Patients uncommonly die from respiratory failure [8]. Numerous studies suggest that survival has improved over time [10,12-14]. As an example, an observational study of 2451 patients who had enrolled in ARDSNet randomized trials found a fall in mortality from 35 to 26 percent between 1996 and 2005 [13]. Although encouraging, several issues should be considered with respect to trends in ARDS-related mortality:

It is not known if mortality has decreased among patients who received their care outside of a specialized center or a clinical trial. The improved mortality may be attributable to patients who have ARDS related to risk factors other than sepsis, such as trauma [12]. To the extent that mortality has decreased, the reasons are uncertain. Likely causes include better supportive care and improved ventilatory strategies, such as low tidal volume ventilation [3,13,15]. (See"Mechanical ventilation in acute respiratory distress syndrome", section on 'Low tidal volume ventilation'.)

Predictors Many studies have sought to identify factors during the acute illness that predict mortality. Such factors can be categorized as patient-, disease-, or treatment-related. No single factor has proven to be superior to the others. Patient-related Older patients appear to be at an increased risk for death [5,16]. This was illustrated by a multicenter cohort study that followed 1113 patients with ARDS for 15 months [5]. The mortality rate increased progressively with age, ranging from 24 percent among patients 15 to 19 years of age to 60 percent among patients 85 years of age or older. The overall mortality rate was 41 percent. Although it has been suggested that obesity may impact the mortality of critically ill patients with or without ARDS, evidence is conflicting [1723].

Disease-related Disease-related predictors of mortality include severe hypoxemia, failure of oxygenation to improve, pulmonary vascular dysfunction, increased dead space, infection, a high severity of illness score, a non-traumatic cause of the ARDS, and certain biomarkers and gene polymorphisms.

Oxygenation The severity of hypoxemia determines whether the patient has mild ARDS (PaO2/FiO2>200 but 300 mmHg), moderate ARDS (PaO2/FiO2 >100 but 200 mmHg), or severe ARDS (PaO2/FiO2100 mmHg). Mortality appears to increase as ARDS becomes more severe, according to an observational study of 3670 patients with ARDS that found that patients with mild, moderate, and severe ARDS had mortality rates of 27, 32, and 45 percent, respectively [24]. Similarly, there is general agreement that improvement of oxygenation during the early ICU course correlates with survival [25]. Pulmonary vascular dysfunction Pulmonary vascular dysfunction is indicated by an elevated transpulmonary gradient (ie, 12 mmHg) or pulmonary vascular resistance index (ie, >285 dyne s/cm).The transpulmonary gradient is the difference between the mean pulmonary artery pressure and the pulmonary artery occlusion pressure, while the pulmonary vascular resistance index is the transpulmonary gradient divided by the cardiac index. Pulmonary vascular dysfunction appears to be an independent risk factor for 60-day mortality and fewer ventilator-free, ICU-free, and hypotensionor vasopressor-free days [26]. Dead space Dead space ventilation early in the course of ARDS appears to correlate with mortality. This was illustrated by a series of 179 patients with early ARDS who had their ratio of dead space to tidal volume (ie, the dead space fraction or Vd/Vt) determined by measuring exhaled carbon dioxide (CO2) levels [27]. The dead space fraction was markedly elevated (mean 0.58, normal <0.30) and there was a linear correlation between the degree of dead space ventilation and mortality. For every 0.05 increase in dead space fraction, the odds of death increased by 45 percent. Infection Infection and/or multiorgan dysfunction are better predictors of mortality than respiratory parameters [12,28-33]. This is probably because they predict death from a nonrespiratory cause, which is more common than death due to respiratory failure. Severity of illness score Severity of illness scores appear to correlate with mortality. As an example, patients with a higher APACHE III score have an increased likelihood of death (odds ratio 1.78 per 25-point increase, 95% CI 1.16-2.73) [16]. (See "Predictive scoring systems in the intensive care unit", section on 'Acute Physiologic and Chronic Health Evaluation (APACHE)'.) Underlying cause of the ARDS Patients with trauma-related ARDS appear to have a lower likelihood of death at 90 days than patients with ARDS that is unrelated to trauma [34]. Severe but not mild or moderate alcohol misuse, in patients with acute lung injury, is associated with an increased risk of death or persistent hospitalization at 90 days (adjusted odds ratio, 1.7; 95% CI 1.00 to 1.87) [35]. Laboratory Routine laboratory parameters are not helpful for predicting the outcome of ARDS. However, a large body of emerging evidence suggests that many biomarkers and gene polymorphisms are associated with both susceptibility to ARDS

and outcome from ARDS [36]. The practical utility of these observations is uncertain, but the research may lead to new preventative and therapeutic strategies in the future. Treatment-related Treatment-related predictors of mortality include a positive fluid balance, glucocorticoid therapy prior to the onset of ARDS, packed red blood cell transfusions, and being in an ICU that does not mandate care by an intensivist.

Fluid balance A positive fluid balance may be associated with higher mortality [37,38]. This was demonstrated by the ARDSNet low tidal volume trial, which found that a negative fluid balance at day 4 was associated with decreased mortality compared to a positive fluid balance, after adjustment for factors such as age, severity of illness, and ventilator strategy (adjusted odds ratio 0.50, 95% CI 0.280.89) [38]. (See "Supportive care and oxygenation in acute respiratory distress syndrome", section on 'Fluid management'.) Treatment with glucocorticoids Patients who received glucocorticoids prior to the onset of ARDS may have an increased likelihood of death (odds ratio 4.65, 95% CI 1.47-14.7) [16]. (See "Novel therapies for the acute respiratory distress syndrome", section on 'Glucocorticoids'.) Packed red blood cell transfusion Patients who receive packed red blood cell transfusions may have an increased likelihood of death (odds ratio 1.10 per unit transfused, 95% CI 1.04-1.17) [16,39]. Organization of the ICU Patients cared for in an ICU that mandates transfer to an intensivist or co-management by an intensivist may have a decreased likelihood of death (odds ratio 0.68, 95% CI 0.53-0.89) [40].

MORBIDITY AMONG SURVIVORS Survivors of ARDS frequently have persistent, abnormal exercise endurance [41-47]. The persistent nature of this abnormality was demonstrated by a prospective cohort study that followed 109 survivors of ARDS for five years [47]. The six minute walking distance at one, three, and five years was 66, 67, and 76 percent of predicted, respectively. Whether this abnormal exercise endurance is due, in part, to decreased lung function is uncertain due to conflicting data. Numerous studies have suggested that there is persistent impairment of lung function following the acute illness [4146], while others have found little or no impairment [47,48]. A constellation of other physical and psychological problems, as well as imaging abnormalities, can occur after the acute illness [43,46-52], many as long as five years after ICU discharge [47]. Examples include new physical disabilities, impaired neurocognitive function, depression, anxiety, pervasive memories of critical care, and changes to relationships, particularly with caregivers [47,53-56]. Such problems appear to be common, with one prospective cohort study estimating that the incidences of depressive symptoms and impaired physical function were 40 and 66 percent, respectively, during the two years following acute lung injury [54]. (See "Management and prognosis of patients requiring prolonged mechanical ventilation", section on 'Outcomes'.) Despite these abnormalities, most survivors are able to return to work. In the prospective cohort study described above, 77 percent of those who were working at the time of their

acute illness returned to work, while 17 percent did unpaid work within the home and six percent became full-time students [47]. Most of those who returned to work did so within two years after ICU discharge, although many required a gradual transition back to work. Several studies have sought factors during the acute illness that predict long-term sequelae [44,48,57,58]:

Persistent symptoms one year after recovery correlate with the duration of mechanical ventilation and the lowest static thoracic compliance during the acute illness [44]. Abnormal lung function one year after recovery correlates with the following factors measured during the acute illness: lowest static thoracic compliance, mean pulmonary artery pressure, positive end-expiratory pressure (PEEP), initial intrapulmonary shunt fraction, and requirement of an FiO2 >0.6 for more than 24 hours [57,58]. A better functional outcome at one year correlates with the absence of steroid treatment, absence of illness acquired during the ICU stay, and rapid resolution of multiple organ failure and lung injury [48]. There is no known correlation between ventilatory strategies and either long-term pulmonary function or health-related quality of life [43,59].

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.)

Basics topics (see "Patient information: Adult respiratory distress syndrome (The Basics)")

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) [11]. 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 [12]. A simplified version of the equation is: Q = K x [(Pmv - Ppmv) - rc (mv - pmv)] 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, mv the oncotic pressure in the circulation, and pmv 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 (figure 1A-D) [12]:

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 ARDS is a consequence of an alveolar injury producing diffuse alveolar damage (picture 2 and picture 3) [13]. The injury causes release of pro-inflammatory cytokines such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-8 [14-19]. 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 [13,20-24]. 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 [25]. The ability to upregulate alveolar fluid clearance may also be lost [26]. 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 ARDS is primarily due to ventilation-perfusion mismatching: physiologic shunting causes hypoxemia, while increased physiologic dead space impairs carbon dioxide elimination [27,28]. 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 ARDS [29]. It is a consequence of the stiffness of poorly or non-aerated lung, rather than the pressure-volume characteristics of residual functioning lung units [30]. Even small tidal volumes can exceed the lung's inspiratory capacity and cause a dramatic rise in airway pressures [29].

Pulmonary hypertension Pulmonary hypertension (PH) occurs in up to 25 percent of patients with ARDS who undergo mechanical ventilation [31-33]. Causes include hypoxic vasoconstriction, vascular compression by positive airway pressure, parenchymal destruction, airway collapse, hypercarbia, and pulmonary vasoconstrictors [34]. The clinical importance of PH in most patients with ARDS is uncertain. PH severe enough to cor pulmonale is rare, but it is associated with an increased risk of death [35,36].

Increased airways resistance (Raw) is also a feature of ARDS, although its clinical significance is uncertain [37,38]. PATHOLOGIC STAGES Patients with ARDS tend to progress through three relatively discrete pathologic stages (figure 2) [39]. 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 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 ARDS was due to a pulmonary process than when it was due to an extrapulmonary precipitant, such as sepsis [40-43]. More than 60 possible causes of 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 ARDS [8,44-47]. Factors that may predispose a patient to develop ARDS, but probably can't cause ARDS, have also been identified. Sepsis Sepsis is the most common cause of ARDS [44,45,48,49]. It should be the first etiology considered whenever 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 ARDS may be particularly high among septic patients with a history of alcoholism [50-52]. This was illustrated by a prospective cohort study that determined the incidence of ARDS in 220 patients with septic shock [51]. The incidence of 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 [50,53,54]. Alternatively, chronic alcohol abuse may increase the risk of ARDS by enhancing inappropriate leukocyte adhesion to endothelial cells [55].

Aspiration Observational evidence indicates that ARDS will develop in approximately one-third of hospitalized patients who have a recognized episode of aspiration of gastric contents [44,46,56]. It was initially suggested that aspirated contents had to have a pH less than 2.5 to cause severe lung injury [57]; however, more recent animal studies have shown that aspiration of non-acidic gastric contents can also cause widespread damage to the lungs [58]. This suggests that gastric enzymes and small food particles also contribute to the lung injury. The unexpected development of 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 ARDS that develops outside of the hospital [59]. Common pathogens include Streptococcus pneumoniae [60], Legionella pneumophila, Pneumocystis jirovecii (formerly called Pneumocystis carinii), Staphylococcus aureus, enteric gram negative organisms, and a variety of respiratory viruses [61,62]. (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 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 ARDS is a complication of severe trauma. There are several situations during which ARDS seems to be particularly common following trauma [63]:

Bilateral lung contusion following blunt trauma [64]. Fat embolism after long bone fractures. In this situation, ARDS typically appears 12 to 48 hours after the trauma. This complication has decreased since immobilization for transport to the hospital became routine [65]. (See "Fat embolism syndrome".) Sepsis may be the most common cause of ARDS that develops several days or more after severe trauma or burns. Massive traumatic tissue injury may directly precipitate or predispose a patient to ARDS [63,66].

Although ARDS can contribute to the length of critical illness following severe trauma, it does not appear to independently increase the risk of death [67]. Trauma-related ARDS has a significantly better prognosis than ARDS that is not related to trauma [68]. Massive transfusion Transfusion of more than 15 units of red blood cells is a risk factor for the development of ARDS [45]. It is unknown whether the transfusion injures the lungs or the need for massive transfusion identifies patients who are at high risk for ARDS from other causes [69]. Transfusion of smaller volumes of packed red blood cells may also increase the risk of developing ARDS, as well as increasing the risk of mortality among patients with established ARDS [70]. (See "Massive blood transfusion".)

Transfusion-related acute lung injury Transfusion of even one unit of a plasmacontaining blood product sometimes causes ARDS [71,72]. 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 (TRALI)".) 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 ARDS is attributed to imperfect preservation of the transplanted lung. (See "Primary lung graft dysfunction".) Hematopoietic stem cell transplant patients are at risk for ARDS due to a variety of infectious and noninfectious causes. Noninfectious insults include idiopathic pneumonia syndrome, engraftment syndrome, and diffuse alveolar hemorrhage [73]. 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 ARDS can occur following an overdose. Drugs that have been implicated include aspirin, cocaine, opioids, phenothiazines, and tricyclic antidepressants [74,75]. Idiosyncratic reactions to other drugs (eg, protamine, nitrofurantoin), including certain chemotherapeutic agents, occasionally precipitate ARDS after therapeutic doses. Radiologic contrast media can also provoke ARDS in susceptible individuals [76]. Alcohol abuse increases the risk of ARDS due to other causes (eg, sepsis, trauma), but does not cause ARDS [77]. Genetic determinants It seems likely that there are genetic determinants that increase an individual's risk of developing ARDS, since only a small proportion of the patients who are exposed to typical insults actually develop ARDS [78]. Studies that link mutations in the surfactant protein B (SP-B) gene to an increased risk of ARDS support this notion [79,80]. Insertion-deletion polymorphisms associated with the angiotensin converting enzyme (ACE) gene have also been suggested as a possible risk factor for ARDS [81], although not all studies support this observation [82]. Other risk factors Other possible risk factors for ARDS include cigarette smoking [83,84], cardiopulmonary bypass [85,86], pneumonectomy [87], acute pancreatitis [88], obesity [89,90], and near drowning [56,91,92]. (See "Drowning (submersion injuries)".) Venous air embolism can occasionally cause 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 [93]. (See "Air embolism".) Lung injury prediction score The lung injury prediction score (LIPS) identifies patients who are unlikely to develop ARDS. This was demonstrated by a prospective cohort study of 5584 patients, in which seven percent of the cohort developed ARDS, resulting in a negative predictive value (ie, the percent of patients with a LIPS <4 who will not develop ARDS) of 97 percent [94]. A LIPS >4 predicted ARDS with a sensitivity and specificity of 69 and 78

percent, respectively. A smaller study, using a retrospective derivation and prospective validation cohorts reported similar results [95]. The LIPS is the sum of the points assigned for each of the following predisposing conditions: shock (2 points), aspiration (2 points), sepsis (1 point), pneumonia (1.5 points), orthopedic spine surgery (1.5 points), acute abdominal surgery (2 points), cardiac surgery (2.5 points), aortic vascular surgery (3.5 points), traumatic brain injury (2 points), smoke inhalation (2 points), near drowning (2 points), lung contusion (1.5 points), multiple fractures (1.5 points), alcohol abuse (1 point), obesity (BMI >30, 1 point), hypoalbuminemia (1 point), chemotherapy (1 point), fraction of inspired oxygen >0.35 or >4 L/min (2 points), tachypnea >30 breaths/min (1.5 points), oxyhemoglobin saturation <95 percent (1 point), acidosis (pH <7.35, 1.5 points), and diabetes mellitus (-1 point). INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.)

Basics topics (see "Patient information: Adult respiratory distress syndrome (The Basics)")


Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by the acute onset of bilateral alveolar infiltrates and hypoxemia. The diagnostic criteria for ARDS are provided separately. (See "Acute respiratory distress syndrome: Clinical features and diagnosis", section on 'Diagnostic criteria'.) Healthy lungs regulate the movement of fluid to maintain a small amount of interstitial fluid and dry alveoli. In patients with 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 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 ARDS.

Factors that may predispose a patient to develop ARDS have also been identified. (See 'Etiologies and predisposing factors' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2:319. 2. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS.