Acute Respiratory Distress Syndrome
Background
Since World War I, it has been recognized that some patients with nonthoracic injuries, severe pancreatitis, massive transfusion, sepsis, and other conditions may 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 However, clear definition of the syndrome was needed to allow research into its pathogenesis and treatment. 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 rather than adult respiratory distress syndrome was used 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. Based on the AECC, ARDS is defined as an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence for cardiogenic pulmonary edema. By these criteria, the severity of hypoxemia necessary to make the diagnosis of ARDS is defined by the PaO2/FiO2 ration, the ratio of the partial pressure of oxygen in the patient's arterial blood to the fraction of oxygen in the inspired air. In ARDS, this ratio is less than 200, and in acute lung injury (ALI), this ratio is less than 300. In addition, cardiogenic pulmonary edema must be excluded either by clinical criteria or pulmonary capillary wedge pressure of less than 18 mm Hg in patients with a 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, comprising 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 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 an important role in the pathogenesis of ARDS. Evidence for this comes from studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS. Despite the apparent importance of neutrophils in ARDS, the syndrome may develop in profoundly neutropenic patients, and infusion of granulocyte colony-stimulating factor (GCSF) in patients with ventilator-associated pneumonia does not promote the development of ARDS. This and other evidence suggest to some that the neutrophils observed in ARDS may be reactive rather than causative.
Cytokines, such as tumor necrosis factor (TNF), leukotrienes, macrophage inhibitory factor, and numerous others, along with platelet sequestration and activation, also are 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.
ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, 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 by 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 ventilator-associated lung injury.
ARDS causes marked increase in intrapulmonary shunt, leading to severe hypoxemia. Although high inspired oxygen concentrations are required to maintain adequate tissue oxygenation and life, additional measures, like lung recruitment with positive end-expiratory pressure (PEEP), is often required. Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity. Generally, oxygen concentrations greater 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.
Since World War I, it has been recognized that some patients with nonthoracic injuries, severe pancreatitis, massive transfusion, sepsis, and other conditions may 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 However, clear definition of the syndrome was needed to allow research into its pathogenesis and treatment. 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 rather than adult respiratory distress syndrome was used 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. Based on the AECC, ARDS is defined as an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence for cardiogenic pulmonary edema. By these criteria, the severity of hypoxemia necessary to make the diagnosis of ARDS is defined by the PaO2/FiO2 ration, the ratio of the partial pressure of oxygen in the patient's arterial blood to the fraction of oxygen in the inspired air. In ARDS, this ratio is less than 200, and in acute lung injury (ALI), this ratio is less than 300. In addition, cardiogenic pulmonary edema must be excluded either by clinical criteria or pulmonary capillary wedge pressure of less than 18 mm Hg in patients with a 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, comprising 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 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 an important role in the pathogenesis of ARDS. Evidence for this comes from studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS. Despite the apparent importance of neutrophils in ARDS, the syndrome may develop in profoundly neutropenic patients, and infusion of granulocyte colony-stimulating factor (GCSF) in patients with ventilator-associated pneumonia does not promote the development of ARDS. This and other evidence suggest to some that the neutrophils observed in ARDS may be reactive rather than causative.
Cytokines, such as tumor necrosis factor (TNF), leukotrienes, macrophage inhibitory factor, and numerous others, along with platelet sequestration and activation, also are 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.
ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, 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 by 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 ventilator-associated lung injury.
ARDS causes marked increase in intrapulmonary shunt, leading to severe hypoxemia. Although high inspired oxygen concentrations are required to maintain adequate tissue oxygenation and life, additional measures, like lung recruitment with positive end-expiratory pressure (PEEP), is often required. Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity. Generally, oxygen concentrations greater 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.
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 a much lower incidence, about a tenth of the previous figure. The first study to use the 1994 AECC definitions was performed in Scandinavia, which again reported a relatively higher incidence of 17.9 cases per 100,000 population for ALI and 13.5 cases per 100,000 population for ARDS.2
Based on data obtained over the last several years by the NIH-sponsored ARDS Study Network, the incidence of ARDS may actually be more than the original estimate of 75 cases per 100,000 population. A prospective study using the 1994 definition was performed in King County, Washington from April 1999 through July 2000 and found that the age-adjusted incidence of acute lung injury was 86.2 per 100,000 person-years.3 Incidence increased with age reaching 306 per 100,000 person-years for people in aged 75-84 years. Based on these statistics, it is estimated that 190,600 cases exist in the United States annually, associated with 74,500 deaths.
International
See US frequency.
Mortality/Morbidity
Until the 1990s, most studies reported a mortality rate for ARDS of 40-70%. 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%.4, 5 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. Mortality in ARDS increases with advancing age. The study performed in King County, Wash found a mortality rate of 24% in patients between ages 15 and 19 years and 60% in patients aged 85 years and older.
Morbidity is considerable. Patients with ARDS are likely to have prolonged hospital courses, and they frequently develop nosocomial infections, especially ventilator-associated pneumonia. In addition, patients often have significant weight loss and muscle weakness and functional impairment may persist for months following hospital discharge.6
Note that most of the deaths in ARDS are attributable to sepsis or multiorgan failure rather than 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.
Some factors that predict the risk of death include advanced age, chronic liver disease, extrapulmonary organ dysfunction and/or failure, sepsis, and elevated levels of PCP-III, a marker of pulmonary fibrosis, in the BAL fluid.
Indices of oxygenation and ventilation, including the PaO2/FIO2 ratio, do not predict the outcome or risk of death. However, a poor prognostic factor is the failure of pulmonary function to improve in the first week of treatment.
Sex
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, a slight preponderance of the disease may occur in females.
Age
ARDS may occur in people of any age. The age distribution reflects the incidence of the underlying causes. As noted above, the incidence of ARDS increases with advancing age. It ranges from 16 per 100,000 person-years in those aged 15-19 years to 306 per 100,000 person-years in those between the ages of 75 and 84 years
History
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 initial event is obvious, but, in others (eg, drug overdose), the underlying cause may not be so obvious.
Patients developing ARDS are critically ill, often with multisystem organ failure, and they may not be capable of providing historical information.
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, the 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
Physical findings often are nonspecific and include tachypnea, tachycardia, and the need for high inspired oxygen concentrations 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.
Because the patient is often intubated and mechanically ventilated, decreased breath sounds over one lung may indicate a pneumothorax or endotracheal tube down the right main bronchus.
Manifestations of the underlying cause, such as acute abdominal findings in 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 decubiti 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 distension, cardiac murmurs and gallops, hepatomegaly, and edema.
Rales may not be present despite widespread involvement.
Causes
Risk factors for ARDS include direct lung injury, systemic illnesses, and injuries.
The most common risk factor for ARDS is sepsis. Other nonthoracic conditions contributing to the risk for developing ARDS include trauma with or without massive transfusion, acute pancreatitis, drug overdose, and long bone fracture.
The most common direct lung injury associated with ARDS is aspiration of gastric contents.
Other risk factors include various viral and bacterial pneumonias, near drowning, and toxic inhalations.
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 acute physiology and chronic health evaluation (APACHE) increases the risk of development of ARDS.
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 initial event is obvious, but, in others (eg, drug overdose), the underlying cause may not be so obvious.
Patients developing ARDS are critically ill, often with multisystem organ failure, and they may not be capable of providing historical information.
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, the 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
Physical findings often are nonspecific and include tachypnea, tachycardia, and the need for high inspired oxygen concentrations 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.
Because the patient is often intubated and mechanically ventilated, decreased breath sounds over one lung may indicate a pneumothorax or endotracheal tube down the right main bronchus.
Manifestations of the underlying cause, such as acute abdominal findings in 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 decubiti 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 distension, cardiac murmurs and gallops, hepatomegaly, and edema.
Rales may not be present despite widespread involvement.
Causes
Risk factors for ARDS include direct lung injury, systemic illnesses, and injuries.
The most common risk factor for ARDS is sepsis. Other nonthoracic conditions contributing to the risk for developing ARDS include trauma with or without massive transfusion, acute pancreatitis, drug overdose, and long bone fracture.
The most common direct lung injury associated with ARDS is aspiration of gastric contents.
Other risk factors include various viral and bacterial pneumonias, near drowning, and toxic inhalations.
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 acute physiology and chronic health evaluation (APACHE) increases the risk of development of ARDS.
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