Acute Respiratory Distress Syndrome

Background: Since World War I, it has been recognized that some patients with nonthoracic injuries, 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 described 12 such patients in 1967, using the term adult respiratory distress syndrome to describe this condition. 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 damage to the alveoli and lung capillary endothelium. 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 is 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 is associated with severe hypoxemia; therefore, high inspired oxygen concentrations are required to maintain adequate tissue oxygenation and life. Unfortunately, oxygen toxicity may promote further lung injury. Generally, oxygen concentrations greater than 65% for prolonged periods (days) result in diffuse alveolar damage, 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:

• In the US: 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.

  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, Wash 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 (Rubenfeld, 2003). 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.

• Internationally: 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%. 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 (Herridge, 2003).

• 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 appears 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.

Treatment
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.

Other important interventions in sepsis include tight glucose control, use of stress dose corticosteroids, 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. With the development of the NIH-sponsored ARDS Study Network, large well-controlled trials of ARDS therapies are underway. 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

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. While inducing intravascular volume depletion is not recommended, avoiding volume overload is important because volume overload may contribute to a worsened outcome in ARDS. Maintaining a low-normal intravascular volume may be facilitated by hemodynamic monitoring with a Swan-Ganz catheter, aiming for a pulmonary capillary wedge pressures in the range of 12-15 mm Hg. 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 venovenous hemofiltration/dialysis (CVVHD) may be required. More information should soon be available from an ARDS Network trial comparing a dry versus wet fluid management strategy while at the same time comparing whether this
is best just by central venous pressure or by Swan-Ganz catheter.

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% (ARDS Network, 2000).

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 (1998), is the so-called open lung approach, in which the appropriate level is determined by the construction of a static pressure volume curve. 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 (Brower, 2004).

• 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 (2000) 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. 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 (Derdak, 2002). 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 (Kacmarek, 2006).

• 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 (Gattinoni, 2001), 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. 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 (Guerin, 2004), 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.

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.

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
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. 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.

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. 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. 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.

Drug Name	Methylprednisolone (Solu-Medrol) -- High-dose methylprednisolone has been used in trials of patients with ARDS who have persistent pulmonary infiltrates, fever, and high oxygen requirement despite resolution of pulmonary or extrapulmonary infection. Pulmonary infection is assessed with bronchoscopy and bilateral BAL and quantitative culture.
Adult Dose	2 mg/kg/d IV in divided doses
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active tuberculosis; uncontrolled bacterial, viral, fungal, or tubercular infection
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use Depo-Medrol contains benzyl alcohol which is potentially toxic when administered locally to neural tissue; administration of Depo-Medrol by other than indicated routes, including the epidural route, has been associated with reports of serious medical events including arachnoiditis, meningitis, paraparesis/paraplegia, sensory disturbances, bowel/bladder dysfunction, seizures, visual impairment including blindness, ocular and periocular inflammation, and residue or slough at injection site