Acute Respiratory Distress Syndrome

• 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 UK, suggested much lower mortality rates, in the 30-40% range. 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 the critically ill patients.

• It should be noted that most of the deaths in ARDS are attributable to sepsis or multiorgan failure rather than a primary pulmonary cause, though 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/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 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, there appears to be no differences in the incidence between males and females. However, in trauma patients only, there may be a slight preponderance of the disease in females.

• 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 is manifested within 12-48 hours after the inciting event, though, in rare instances, 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.

• As ARDS often occurs in the context of sepsis, there may be associated hypotension and peripheral vasoconstriction with cold extremities.

• There may be cyanosis of the lips and nailbeds. Examination of the lungs may reveal bilateral rales.

• As the patient often is intubated and mechanically ventilated, decreased breath sounds over 1 lung may indicate a pneumothorax or endotracheal tube down the right main bronchus.

• There will be manifestations of the underlying cause, such as acute abdominal findings in pancreatitis.

• In a septic patient without an obvious source, careful attention should be paid 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 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

• ARDS is a clinical diagnosis, and there are no specific laboratory abnormalities noted beyond the expected disturbances in gas exchange and radiographic findings. Other abnormalities observed are dependent upon 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 x-ray (CXR) 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 the patient with ARDS. However, a CT scan maybe indicated in some situations.

• The CT scan is more sensitive than plain chest radiography in picking up pulmonary interstitial emphysema (PIE), 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 pulmonary artery (Swan-Ganz) catheter

• Because the differential diagnosis of ARDS includes cardiogenic pulmonary edema, hemodynamic monitoring with the Swan-Ganz catheter often is helpful 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, right ventricular, pulmonary artery, 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 usually is 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 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.

• Because there is some evidence that keeping patients dry may be beneficial in the management of ARDS, the use of the 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. Hemodynamic monitoring has not been studied in a rigorous, prospective, controlled fashion in patients with ARDS. One large study of critically ill patients monitored with pulmonary artery catheters in the first 24 hours of intensive care admission showed that patients with catheters had an increased mortality rate, hospital cost, and length of stay compared to a retrospectively developed matched patient group managed without them. Certainly, a survival benefit associated with hemodynamic monitoring has not been demonstrated. In addition, accurate measurement of hemodynamic parameters with the Swan-Ganz catheter requires skill and care. This is especially difficult in patients on mechanical ventilation 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 quantitatively cultured.

• Ten thousand organisms per mL 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 also is 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.

• Cytologic evaluation of the BAL fluid also may 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.

• Noninvasive ventilation: Because intubation and mechanical ventilation may be associated with an increased incidence of complications, such as barotrauma and nosocomial pneumonia, there may be an advantage in patients at the milder end of the spectrum of ARDS to 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]). Noninvasive ventilation has been studied best in patients with hypercapnic respiratory failure due to chronic obstructive pulmonary disease (COPD) or neuromuscular weakness; however, in a small series of patients with ARDS, some patients may avoid intubation using this technique.

  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 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, oxygen saturations should be maintained in the 85-90% range 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.

  There is now evidence that a protective ventilation strategy employing low tidal volumes improves survival rates compared to 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 cc per kg of predicted body weight and an inspiratory pressure of 50 cm or less versus a tidal volume of 6 cc/kg and an inspiratory pressure of 30 cm 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% vs 39.8%).

  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 cc per kg predicted body weight is recommended, with adjustment of the tidal volume to as low as 4 cc/kg if needed to limit the inspiratory plateau pressure to 30 cm of water or less.

  The ventilator rate should be increased and bicarbonate administered as needed to maintain the pH at a near normal level. In the ARDS Network Study, patients ventilated with lower tidal volumes required higher levels of PEEP (9.4 vs 8.6 cm) to maintain oxygen saturation at 85% or more. Some authors have speculated that the higher levels of PEEP also may have contributed to the improved survival rates.

• PEEP or CPAP: 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 takes a spontaneous breath, airway pressure decreases to below zero to trigger airflow. With CPAP, a low-resistance demand valve is used in a way that positive pressure is maintained continuously. Positive pressure ventilation increases intrathoracic pressure and, thus, may decrease cardiac output and blood pressure. As 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 usually is used rather than PEEP. It is thought that the use of appropriate levels of CPAP improves outcome in ARDS and, by maintaining alveoli in an expanded state throughout the respiratory cycle, 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. 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 cm.

• Pressure controlled ventilation (PCV): 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 upon lung compliance and increases as ARDS improves. PCV also may 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 utilized. PCV also may be beneficial in patients with bronchopleural fistulae. Ventilation at low peak inspiratory pressures may allow closure. There is evidence 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. A larger trial is needed before a definite recommendation is made.

• Prone position: Sixty to 75% of patients with ARDS have significantly improved oxygenation when turned from the supine to the prone position. The improvement in oxygenation is rapid and often significant enough to allow reductions in FIO₂ or level of CPAP. The prone position may be most effective when used early but still may provide benefit later in the course of ARDS. It 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 failed to 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. However, in a recent randomized controlled trial of the prone position in ARDS, survival to discharge from the ICU
  and survival at 6 months was unchanged compared with care in the supine position, despite a significant improvement in oxygenation. Further study may still be required as the patients in this study were kept in the prone position for only 7 hours per day.

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 eventually is required.

Extracorporeal membrane oxygenation (ECMO) was shown in a large multicenter trial in the 1970's not to improve mortality 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, a physician specializing in pulmonary medicine or critical care should be consulted.

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 shown to improve outcome in ARDS.

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 suffered 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, also may prevent some ARDS cases.

Complications:

• Mechanical ventilation

• 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 manifested by 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.

• Patients with ARDS commonly have intravenous monitoring and access lines, including pulmonary artery catheters and central venous lines. Potential complications of these lines include sepsis and site-specific complications, such as pneumothorax for internal jugular and subclavian lines and infection for femoral lines.

• Nosocomial infection is a significant potential complication of ARDS. In addition to ventilator-associated pneumonia and line sepsis already noted, other potential infection sources include the urinary tract secondary to indwelling urinary catheters, indwelling arterial catheters, and the paranasal sinuses, which may not drain well secondary to nasal tubes.

• 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, usually is the cause of death in ARDS.

• Other potential complications include ileus, stress gastritis, anemia, and critical illness myopathy. Critical illness myopathy may be potentiated by the use of neuromuscular paralyzing agents and corticosteroids. Stress ulcer prophylaxis may also be beneficial.

Prognosis:

• As previously noted, the prognosis of ARDS has improved over the last 20 years. Sixty to 70% survive.

• Poor prognostic factors include being older than 65 years and having 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 a residual restrictive ventilatory defect and a mildly reduced health-related quality of life and have normal or mildly diminished pulmonary function by 1 year after resolution of the acute event. The residual impairment is a restrictive ventilatory defect characterized by diminished lung volumes and diffusing capacity.

• 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.

MISCELLANEOUS

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, careful attention should be paid 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, meticulous care must be taken 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 essential in when paralytic
  agents are in use.

• As in all situations in which patients are critically ill, the family and friends are very concerned and experiencing stress. Keep them informed and let them come to the 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.