AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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.

Frequency

United States

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.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Pulmonary hemorrhage
Near drowning
Drug reaction
Noncardiogenic pulmonary edema
Hamman-Rich syndrome
Retinoic acid syndrome
Acute hypersensitivity pneumonitis
Transfusion-related acute lung injury (TRALI)
Acute eosinophilic pneumonia
Reperfusion injury
Leukemic infiltration
Fat embolism syndrome

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• In addition to hypoxemia, arterial blood gases often initially show a respiratory alkalosis. However, in ARDS occurring in the context of sepsis, a metabolic acidosis with or without respiratory compensation may be present. As the condition progresses and the work of breathing increases, the partial pressure of carbon dioxide (PCO₂) begins to rise and respiratory alkalosis gives way to respiratory acidosis. Patients on mechanical ventilation for ARDS may be allowed to remain hypercapnic (permissive hypercapnia) to achieve the goals of low tidal volume and limited plateau pressure ventilator strategies aimed at limiting ventilator-associated lung injury.
• ARDS is a clinical diagnosis, and no specific laboratory abnormalities are noted beyond the expected disturbances in gas exchange and radiographic findings. ARDS is defined by a PaO₂/FiO₂ ratio of less than 200 and ALI by a ratio of less than 300. Other abnormalities observed depend on the underlying cause or associated complications and may include the following:
• • Hematologic: In septic patients, leukopenia or leukocytosis may be noted. Thrombocytopenia may be observed in septic patients in the presence of disseminated intravascular coagulation (DIC). Von Willebrand factor (VWF) may be elevated in patients at risk for ARDS and may be a marker of endothelial injury.
  • Renal: Acute tubular necrosis (ATN) often ensues in the course of ARDS, probably from ischemia to the kidneys. Renal function should be closely monitored.
  • Hepatic: Liver function abnormalities may be noted in either a pattern of hepatocellular injury or cholestasis.
  • Cytokines: Multiple cytokines, such as IL-1, IL-6, and IL-8, are elevated in the serum of patients at risk for ARDS.

Imaging Studies

• Radiographic manifestations
• • ARDS is defined by the presence of bilateral pulmonary infiltrates. The infiltrates may be diffuse and symmetric or asymmetric, especially if superimposed upon preexisting lung disease or if the insult causing ARDS was a pulmonary process, such as aspiration or lung contusion.
  • The pulmonary infiltrates usually evolve rapidly, with maximal severity within the first 3 days. Infiltrates can be noted on chest radiograph almost immediately after the onset of gas exchange abnormalities. Infiltrates may be interstitial, characterized by alveolar filling, or both.
  • Initially, the infiltrates may have a patchy peripheral distribution but soon progress to diffuse bilateral involvement with ground glass changes or frank alveolar infiltrates.
  • The correlation between radiographic findings and severity of hypoxemia is highly variable. Also, diuresis tends to improve infiltrates and volume overload tends to worsen them, irrespective of improvement or worsening in underlying ARDS.
  • For patients who begin to improve and show signs of resolution, improvement in radiographic abnormalities generally occurs over 10-14 days, but more protracted courses are common.
• CT scans
• • In general, clinical evaluation and routine chest radiography are sufficient in patients with ARDS. However, a CT scan may be indicated in some situations.
  • The CT scan is more sensitive than plain chest radiography in detecting pulmonary interstitial emphysema, pneumothoraces and pneumomediastinum, pleural effusions, cavitation, and mediastinal lymphadenopathy.
  • In some instances, the discovery of unexpected pulmonary pathology, such as a pneumothorax, may be lifesaving. However, this potential benefit must be weighed against the risk associated with transporting a critically ill patient on high-intensity mechanical ventilation out of the intensive care unit to the CT scan equipment.
  • The heterogeneity of alveolar involvement is often apparent on CT scan even in the presence of diffuse homogeneous infiltrates on routine chest radiograph.

Other Tests

• ARDS is defined by the acute onset of bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence of cardiogenic pulmonary edema.
• In ARDS, if the PaO₂ is divided by the FIO₂, the result is 200 or less. For patients breathing 100% oxygen, this means that the PaO₂ is less than 200.

Procedures

• Hemodynamic monitoring with central venous or pulmonary artery (Swan-Ganz) catheter
• • Because the differential diagnosis of ARDS includes cardiogenic pulmonary edema, hemodynamic monitoring with the Swan-Ganz catheter may be helpful in selected cases in separating cardiogenic from noncardiogenic pulmonary edema. The pulmonary artery catheter is floated through an introducer that is placed in a central vein, usually the right internal jugular or subclavian vein. With the balloon inflated, the catheter is advanced with continuous pressure monitoring. This allows measurement of right atrial pressure, right ventricular pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP). With the catheter properly positioned, the PCWP reflects filling pressures on the left side of the heart and, indirectly, intravascular volume status. A PCWP of less than 18 mm Hg is usually consistent with noncardiogenic pulmonary edema, although other factors, such as a low plasma oncotic pressure, may allow cardiogenic pulmonary edema to occur at lower pressures.
  • The pulmonary artery catheter also provides other information that may be helpful in both the differential diagnosis and the treatment of these patients. For example, the calculation of systemic vascular resistance based upon thermodilution cardiac output, right atrial pressure, and mean arterial pressure may provide support for the clinical suspicion of sepsis. The use of mixed venous oxygen saturation to allow the calculation of shunt and oxygen delivery is used by some to adjust ventilator parameters and vasoactive support. Mixed venous oxygen saturation is also used in goal-directed therapy for sepsis.
  • Because avoiding fluid-overload may be beneficial in the management of ARDS, the use of a central venous catheter or pulmonary artery (Swan-Ganz) catheter may facilitate appropriate fluid management in these patients in whom judging intravascular volume status on clinical grounds may be difficult or impossible. This may be especially helpful in patients who are hypotensive or those with associated renal failure.
  • Although Swan-Ganz catheters provide considerable information, their use is not without controversy
  • • The ARDS Clinical Trials Network studied whether a difference in mortality could be found in patients with ARDS whose fluid management was guided by pulmonary artery catheter versus central venous catheter after initial resuscitation had been completed.⁷ The study found no difference in mortality, ventilator days, ICU days, need for pressors or dialysis. The pulmonary artery group had twice as many catheter related complications, primarily arrhythmias. 
    • Another large retrospective study of critically ill patients monitored with pulmonary artery catheters in the first 24 hours of intensive care admission showed that patients with PA catheters had an increased mortality rate, hospital cost, and length of stay compared with a retrospectively developed matched patient group managed without them.⁸ Thus, no survival benefit and possibly an adverse effect on survival is associated with the use of the pulmonary artery catheter past the time of initial resuscitation. In addition, accurate measurement of hemodynamic parameters with the Swan-Ganz catheter requires skill and care. This is especially difficult in patients either on mechanical ventilation or with forced spontaneous inspirations because the pressure tracing is affected by intrathoracic pressure. PCWP should be measured at end expiration and from the tracing rather than from digital displays on the bedside monitor.

• Bronchoscopy with BAL or protected specimen brush culture

• • Bronchoscopy may be considered to evaluate the possibility of infection in patients acutely ill with bilateral pulmonary infiltrates. Culture material may be obtained by wedging the bronchoscope in a subsegmental bronchus and collecting the fluid suctioned after instilling large volumes of nonbacteriostatic saline (BAL). The fluid is analyzed for cell differential, cytology, silver stain, and Gram stain and is quantitatively cultured.
  • Ten thousand organisms per milliliter is generally considered significant in a patient not previously treated with antibiotics. The presence of neutrophils in the lavage with intracellular organisms in these cells is also consistent with infection.
  • As noted above, early ARDS is characterized by the presence of neutrophils in the BAL fluid, so the presence of intracellular organisms and the use of quantitative culture are important in establishing infection. An alternative means of obtaining a culture is by means of a protected specimen brush, which is passed through the bronchoscope into a segmental bronchus. Subsequently, the brush is cut off into 1 mL of sterile nonbacteriostatic saline. Culture of 1000 organisms is considered significant.
  • Analysis of the types of cells present in the BAL fluid may be helpful in the differential diagnosis of patients with ARDS. For example, the finding of a high percentage of eosinophils (>20%) in the BAL fluid is consistent with the diagnosis of acute eosinophilic pneumonia. The use of high-dose corticosteroids in these patients may be lifesaving. A high proportion of lymphocytes may be observed in acute hypersensitivity pneumonitis, sarcoidosis, or bronchiolitis obliterans-organizing pneumonia (BOOP). Red cells and hemosiderin-laden macrophages may be observed in pulmonary hemorrhage. Lipid laden macrophages are suggestive of aspiration or lipoid pneumonia.
  • Cytologic evaluation of the BAL fluid may also be helpful in the differential diagnosis of ARDS. This may reveal viral cytopathic changes for example. Silver stain may be helpful in diagnosing an infection, such as Pneumocystis.

Histologic Findings

The histologic changes in ARDS are those of diffuse alveolar damage. An exudative phase occurs in the first several days and is characterized by interstitial edema, alveolar hemorrhage and edema, alveolar collapse, pulmonary capillary congestion, and hyaline membrane formation. These histologic changes are nonspecific and do not provide information that would allow the pathologist to determine the cause of the ARDS. A biopsy performed after several days shows the beginning of organization of the intra-alveolar exudate and repair, the proliferative phase of ARDS, which is characterized by the growth of type 2 pneumocytes in the alveolar walls and the appearance fibroblasts, myofibroblasts, and collagen deposition in the interstitium. The final phase of ARDS is fibrotic. Alveolar walls are thickened by connective tissue rather than edema or cellular infiltrate.

Staging

In the 1980s, Murray and coworkers (1988) developed a lung injury scoring system.⁹ This system was based on 4 parameters, as follows: severity of consolidation based on chest radiograph findings, severity of hypoxemia based on the PaO₂/FIO₂ ratio, lung compliance, and level of PEEP required. This scoring system has proven helpful in clinical research in ARDS.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

No specific therapy for ARDS exists. Treatment of the underlying condition is essential, along with supportive care and appropriate ventilator and fluid management. Because infection is often the underlying cause of ARDS, careful assessment of the patient for infected sites and institution of appropriate antibiotic therapy are essential. In some instances, removal of intravascular lines, drainage of infected fluid collections, or surgical debridement or resection of an infected site, such as the ischemic bowel, may be necessary because sepsis-associated ARDS does not resolve without such management. However, large tidal volume (>6 mL/kg ideal body weight) worsens outcome.

Other important interventions in sepsis might include early goal-directed therapy, tight glucose control, use of drotrecogin alpha in appropriate patients with severe sepsis, and avoidance of complications by means of prophylaxis for deep venous thrombosis and stress ulcer. The use of stress dose steroids in patients with septic shock did not change survival in a recently reported controlled trial.¹⁰ With the development of the NIH-sponsored ARDS Clinical Trials Network, large well-controlled trials of ARDS therapies have been completed. Thus far, the only treatment found to improve survival rates in such a study is a mechanical ventilation strategy using low tidal volumes.

Fluid management

Separating out initial resuscitation, as used for early goal directed therapy, and maintenance fluid therapy is important. Several small trials have demonstrated improved outcome for ARDS in patients treated with diuretics or dialysis to promote a negative fluid balance in the first few days.

An ARDS Clinical Trials Network study of fluid conservative versus fluid liberal strategies in the management of patients with ARDS/ALI did not demonstrate a statistically significant difference in 60 day mortality when patients were stratified into either group 72 hours after presenting in ARDS.¹¹ However, patients treated with the fluid conservative strategy had an improved oxygenation index and lung injury score and an increase in ventilator-free days, without an increase in nonpulmonary organ failures.

Note that the fluid conservative group actually had an even rather than negative fluid balance over the first seven days, leading to the thought that the benefit may have been underestimated. Maintaining a low-normal intravascular volume may be facilitated by hemodynamic monitoring with a central venous or Swan-Ganz catheter, aiming for a CVP or pulmonary capillary wedge pressure at the lower end of normal. Maintaining mean arterial pressure of 65-70 or more may then require pressor administration. Closely monitor urine output and administer diuretics to facilitate a negative fluid balance. In oliguric patients, hemodialysis with ultrafiltration or continuous veno-venous hemofiltration/dialysis (CVVHD) may be required. 

Noninvasive ventilation

Because intubation and mechanical ventilation may be associated with an increased incidence of complications, such as barotrauma and nosocomial pneumonia, noninvasive ventilation by means of a full face mask attached to a ventilator delivering continuous positive airway pressure (CPAP) with or without ventilator breaths or inspiratory pressure support (ie, noninvasive positive pressure ventilation [NIPPV]) in patients with milder ARDS may be advantageous. Noninvasive ventilation has been studied best in patients with hypercapnic respiratory failure caused by chronic obstructive pulmonary disease (COPD) or neuromuscular weakness; however, in a small series of patients with ARDS, some patients may have avoided intubation using this technique. This may be especially useful in immunocompromised patients.

Contraindications to NIPPV include a diminished level of consciousness or other causes of decreased airway protection reflexes, inadequate cough, vomiting or upper gastrointestinal bleeding, inability to properly fit the mask, poor patient cooperation, and hemodynamic instability.

Mechanical ventilation

The goals of mechanical ventilation in ARDS are to maintain oxygenation while avoiding oxygen toxicity and complications of mechanical ventilation. Generally, maintain oxygen saturations in the range of 85-90%, with a goal of diminishing inspired oxygen concentrations to less than 65% within the first 24-48 hours. This almost always necessitates the use of moderate-to-high levels of PEEP.

Mechanical ventilation may promote the development of acute lung injury. Evidence now indicates that a protective ventilation strategy using low tidal volumes improves survival rates compared with conventional tidal volumes. In a study conducted by the ARDS Network, patients with ALI and ARDS were randomized to mechanical ventilation at a tidal volume of 12 mL/kg of predicted body weight and an inspiratory pressure of 50 cm H₂O or less versus a tidal volume of 6 mL/kg and an inspiratory pressure of 30 cm H₂O or less. The study was stopped early after interim analysis of 861 patients demonstrated that subjects in the low tidal volume group had a significantly lower mortality rate, 31% versus 39.8%.¹²

While previous studies employing low tidal volumes allowed patients to be hypercapnic (permissive hypercapnia) and acidotic to achieve the protective ventilation goals of low tidal volume and low inspiratory airway pressure, the ARDS Network Study allowed increases in respiratory rate and administration of bicarbonate to correct acidosis. This may account for the positive outcome in this study compared to earlier studies that had failed to demonstrate a benefit. Thus, mechanical ventilation with a tidal volume of 6 mL/kg predicted body weight is recommended, with adjustment of the tidal volume to as low as 4 mL/kg if needed to limit the inspiratory plateau pressure to 30 cm H₂O or less. Increase the ventilator rate and administer bicarbonate as needed to maintain the pH at a near normal level (7.3).

In the ARDS Network Study, patients ventilated with lower tidal volumes required higher levels of PEEP (9.4 vs 8.6 cm H₂O) to maintain oxygen saturation at 85% or more. Some authors have speculated that the higher levels of PEEP may also have contributed to the improved survival rates. However, a subsequent ARDS study network trial of higher versus lower PEEP levels in patients with ARDS showed no benefit from higher PEEP levels, either in terms of survival or duration of mechanical ventilation.

• Positive end-expiratory pressure or continuous positive airway pressure
• • ARDS is characterized by severe hypoxemia. When oxygenation cannot be maintained despite high inspired oxygen concentrations, the use of CPAP or PEEP usually promotes improved oxygenation, allowing for tapering of the FIO₂. With PEEP, positive pressure is maintained throughout expiration, but when the patient inhales spontaneously, airway pressure decreases to below zero to trigger airflow. With CPAP, a low-resistance demand valve is used to allow positive pressure to be maintained continuously. Positive pressure ventilation increases intrathoracic pressure and, thus, may decrease cardiac output and blood pressure. Because mean airway pressure is greater with CPAP than PEEP, CPAP may have a more profound effect on blood pressure.
  • In general, patients tolerate CPAP well, and CPAP is usually used rather than PEEP. The use of appropriate levels of CPAP is thought to improve the outcome in ARDS. By maintaining the alveoli in an expanded state throughout the respiratory cycle, CPAP may decrease shear forces that promote ventilator-associated lung injury.
  • The best method for finding the optimal level of CPAP in patients with ARDS is controversial. Some favor the use of just enough CPAP to allow reduction of the FIO₂ below 65%.
  • • Another approach, favored by Amato and associates is the so-called open lung approach, in which the appropriate level is determined by the construction of a static pressure volume curve.¹³ This is an S-shaped curve, and the optimal level of PEEP is just above the lower inflection point. Using this approach, the average PEEP level required is 15.
    • However, as noted above, an ARDS Network study of higher versus lower PEEP levels in ARDS demonstrated no advantage to use of higher PEEP levels. In this study, PEEP level was determined by how much inspired oxygen was required to achieve a goal oxygen saturation of 88-95% or goal PO₂ of 55-80 mm Hg. The PEEP level averaged 8 in the lower PEEP group and 13 in the higher PEEP group. No difference was shown in duration of mechanical ventilation or survival to hospital discharge.¹⁴
• Pressure-controlled ventilation and high frequency ventilation
• • If high inspiratory airway pressures are required to deliver even low tidal volumes, pressure-controlled ventilation (PCV) may be initiated. In this mode of mechanical ventilation, the physician sets the level of pressure above CPAP (delta P) and the inspiratory time (I-time) or inspiratory/expiratory (I:E) ratio. The resultant tidal volume depends on lung compliance and increases as ARDS improves. PCV may also result in improved oxygenation in some patients not doing well on volume-controlled ventilation (VCV). If oxygenation is a problem, longer I-times, such that inspiration is longer than expiration (inverse I:E ratio ventilation) may be beneficial. Ratios as high as 4:1 have been used. PCV, using lower peak pressures, may also be beneficial in patients with bronchopleural fistulae, facilitating closure of the fistula.
  • Evidence indicates that PCV may be beneficial in ARDS, even without the special circumstances noted. In a multicenter controlled trial comparing VCV to PCV in patients with ARDS, Esteban found that PCV resulted in fewer organ system failures and lower mortality rates than VCV, despite use of the same tidal volumes and peak inspiratory pressures.¹⁵ A larger trial is needed before a definite recommendation is made.
  • High frequency ventilation (jet or oscillatory) is a ventilator mode that uses low tidal volumes and high respiratory rates. With the knowledge that distension of alveoli is one of the mechanisms promoting ventilator-associated lung injury, high frequency ventilation would be expected to be beneficial in ARDS. Results of clinical trials in adults have generally demonstrated early improvement in oxygenation when compared with conventional ventilation but no improvement in survival. In the largest randomized controlled trial, 148 adults with ARDS were randomized to conventional ventilation or high frequency oscillatory ventilation (HFOV). The HFOV group had early improvement in oxygenation that did not persist beyond 24 hours. The 30-day mortality in the HFOV group was 37% compared with 52% in the conventional ventilation group, but this difference was not statistically significant.¹⁶ This mode of ventilation may be the most useful for patients with bronchopleural fistulae.
  • Partial liquid ventilation has also been tried in ARDS and in a randomized controlled trial in which it was compared with conventional mechanical ventilation, resulted in increased morbidity (pneumothoraces, hypotensions, and hypoxemic episodes), and a trend toward higher mortality.¹⁷
• Prone position
• • Although, 60-75% of patients with ARDS have significantly improved oxygenation when turned from the supine to the prone position, no survival benefit exists for patients treated in the prone position. When the prone position is used, the improvement in oxygenation is rapid and often significant enough to allow reductions in FIO₂ or level of CPAP. The prone position is safe, with appropriate precautions to secure all tubes and lines, and does not require special equipment. The improvement in oxygenation may persist after the patient is returned to the supine position and may occur on repeat trials in patients who did not respond initially.
  • Possible mechanisms for the improvement noted are recruitment of dependent lung zones, increased functional residual capacity (FRC), improved diaphragmatic excursion, increased cardiac output, and improved ventilation-perfusion matching.
  • • Despite improved oxygenation with the prone position, randomized controlled trial of the prone position in ARDS have not demonstrated improved survival. In an Italian study, the survival rate to discharge from the ICU and the survival rate at 6 months were unchanged compared with patients who underwent care in the supine position, despite a significant improvement in oxygenation.¹⁸ This study was criticized because patients were kept in the prone position for an average of only 7 hours per day.
    • However, in a subsequent French study in which patients were in the prone position for at least 8 hours per day, no benefit was shown to the prone position in terms of 28 day or 90 day mortality, duration of mechanical ventilation, or development of ventilator-associated pneumonia.¹⁹

Surgical Care

The treatment of ARDS is medical. Surgical intervention may be required for some of the underlying causes of ARDS, as previously noted. In patients requiring prolonged mechanical ventilation, tracheostomy is eventually required.

Extracorporeal membrane oxygenation (ECMO) was demonstrated in a large multicenter trial in the 1970s not to improve the mortality rate in ARDS. Still, it remains a potential heroic measure in select cases.

Consultations

Treatment of patients with ARDS requires special expertise with mechanical ventilation and management of critical illness. Thus, consult a physician specializing in pulmonary medicine or critical care.

Diet

Institution of nutritional support after 48-72 hours of mechanical ventilation usually is recommended. Unless contraindicated because of an acute abdomen, ileus, gastrointestinal bleeding, or other conditions, enteral nutrition via a feeding tube is preferable to intravenous hyperalimentation. A low-carbohydrate high-fat enteral formula containing components that are anti-inflammatory and vasodilating (eicosapentaenoic acid and linoleic acid) with antioxidants has been demonstrated in some studies to improve outcome in ARDS.^{20, 21} In a prospective, randomized study of ARDS patients fed with an enteral nutrition formula containing antioxidants, eicosapentaenoic acid, and gamma-linoleic acid compared with a standard isocaloric formula, Pontes-Arruda demonstrated improved survival and oxygenation in patients receiving the specialized diet.

Activity

Patients with ARDS are at bedrest. Frequent position change and passive and, if possible, active range of motion activities of all muscle groups should be started immediately. Elevation of the head of the bed to a 45° angle is recommended to diminish the development of ventilator-associated pneumonia.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

No drug has proved beneficial in the prevention or management of ARDS. The early administration of corticosteroids in septic patients does not prevent the development of ARDS. Numerous pharmacologic therapies, including the use of inhaled synthetic surfactant, intravenous antibody to endotoxin, ketoconazole, and ibuprofen, have been tried and are not effective.²² Small sepsis trials suggest a potential role for antibody to TNF and recombinant IL-1 receptor antagonist. Inhaled nitric oxide (NO), a potent pulmonary vasodilator seemed promising in early trials, but in larger controlled trials, did not change mortality rates in adults with ARDS.^{23, 24}

It was thought that there might be a role for high-dose corticosteroid therapy in patients with late (fibroproliferative phase) ARDS, because of apparent benefit in small trials.²⁵ However, an ARDS Study Network trial of methylprednisolone for patients with ARDS persistent for at least 7 days demonstrated no benefit in terms of 60-day mortality.²⁶ Patients treated late, 14 days after onset, had worsened mortality with corticosteroid therapy. Although no survival advantage was shown in patients treated with methylprednisolone, short-term clinical benefits included improved oxygenation and increased ventilator-free and shock-free days. Patients treated with corticosteroids were more likely to experience neuromuscular weakness, but the rate of infectious complications was not increased.

Drug Category: Corticosteroids

Development of the late phase of ARDS may represent continued uncontrolled inflammation and corticosteroids may be considered a form of rescue therapy that may improve oxygenation and hemodynamics but does not change mortality, except that corticosteroids increase mortality in patients with ARDS for more than 14 days.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

Once the acute phase of ARDS resolves, patients may require a prolonged period to wean from mechanical ventilation and to regain muscle strength lost after prolonged inactivity. This may necessitate transfer to a rehabilitation facility once the acute phase of the illness is resolved.

Transfer

• Transfer to a tertiary care facility may be indicated in ARDS in some situations, if safe transport can be arranged.
• • Transfer may be indicated if inspired oxygen concentrations cannot be weaned to less than 0.65 within 48 hours.
  • Other patients who may potentially benefit from transfer include those who have experienced pneumothorax and have persistent air leaks, patients who cannot be weaned from mechanical ventilation, patients who have upper airway obstruction after prolonged intubation, or those with a progressive course in which an underlying cause cannot be identified.
  • If ARDS develops in a patient who previously has undergone organ or bone marrow transplantation, transfer to an experienced transplant center is essential for appropriate management.

Deterrence/Prevention

• While multiple risk factors for ARDS are known, no successful preventative measure has been identified.
• Careful fluid management in high-risk patients may be helpful.
• Because aspiration pneumonitis is a risk factor for ARDS, taking appropriate measures to prevent aspiration, such as elevation of the head of the bed and evaluation of swallowing mechanics before feeding high-risk patients, may also prevent some ARDS cases.

Complications

• Patients with ARDS often require high-intensity mechanical ventilation, including high levels of PEEP or CPAP and, possibly, high mean airway pressures; thus, barotrauma may occur. Patients present with pneumomediastinum and/or pneumothorax. Other potential complications that may occur in these mechanically ventilated patients include accidental extubation, right mainstem intubation, and ventilator-associated pneumonia. 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.
• Nosocomial infections: As 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 may be as high as 55% and appears to be higher than in other populations requiring mechanical ventilation. Preventative strategies including elevation of head of the bed, use of subglottic suction endotracheal tubes, and oral decontamination.
• Other potential infections include urinary tract infection 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 duration of ICU stay and treatment with multiple antibiotics, may also develop infections with drug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE).
• Muscle weakness: In a study of survivors of ARDS, significant functional impairment was noted at 1 year, primarily related to muscle wasting and weakness.⁶ Corticosteroid treatment and use of neuromuscular blockade are risk factors for muscle weakness and poor functional recovery.
• Prolonged mechanical ventilation: Patients may have difficulty weaning from mechanical ventilation. Strategies to facilitate weaning, such as daily interruption of sedation, 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).

Prognosis

• As previously noted, the prognosis of ARDS has improved over the last 20 years. Sixty to 70% of patients survive.
• Patients with poor prognostic factors include those older than 65 years and those with sepsis as the underlying cause. The adverse effect of age may be related to underlying health status.
• The severity of hypoxemia at the time of diagnosis does not correlate well with survival rates.
• Survivors of ARDS frequently have significant functional impairment even 1 year after discharge. In a study of 109 survivors, spirometry and lung volumes were normal at 6 months, but diffusing capacity remained mildly diminished (72%) at 1 year.⁶ 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 also completely resolve within a year of recovery.
• Severe disease and prolonged duration of mechanical ventilation are predictors of persistent abnormalities in pulmonary function.

Patient Education

For excellent patient education resources, visit eMedicine's Lung and Airway Center, Procedures Center, and Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Acute Respiratory Distress Syndrome, Bronchoscopy, and Severe Acute Respiratory Syndrome (SARS).

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• The main concerns are missing a potentially treatable underlying cause or complication of ARDS, such as a drainable infection or a pneumothorax. In these critically ill patients, pay careful attention to early recognition of potential complications in the intensive care unit, including pneumothorax, intravenous line infections, skin breakdown, inadequate nutrition, arterial occlusion at the site of intra-arterial monitoring devices, deep venous thrombophlebitis and pulmonary embolism, retroperitoneal hemorrhage, gastrointestinal hemorrhage, erroneous placement of lines and tubes, and the development of muscle weakness.
• In situations in which the patient requires the use of paralyzing agents to allow certain modes of mechanical ventilation, take meticulous care to ensure that an adequate alarm system is in place to alert staff to mechanical ventilator disconnection or malfunction. In addition, adequate sedation is important in most patients on ventilators and is essential when paralytic agents are in use.
• As in all situations in which patients are critically ill, the family and friends are very concerned and experience stress. Keep them informed and let them come to the patient's bedside as much as possible if they desire. Even if the patient is sedated, assume that he or she is capable of hearing and understanding all conversations in the room and is treated with respect and care. The sedated patient may experience pain and should receive appropriate local anesthesia and pain medication for procedures.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Rajat Walia, MD to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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