1. Acute Respiratory Distress Syndrome

2. Background

3. Since World War I, it has been recognized that some patients with non-thoracic injuries, severe pancreatitis, massive transfusion, sepsis, and other conditions develop respiratory distress, diffuse lung infiltrates, and respiratory failure, sometimes after a delay of hours to days.
Ashbaugh et al described 12 such patients in 1967, using the term “adult respiratory distress syndrome” to describe this condition.

4. Before research into the pathogenesis and treatment of this syndrome could proceed, it was necessary to formulate a clear definition of the syndrome.
Such a definition was developed in 1994 by the American- European Consensus Conference (AECC) on acute respiratory distress syndrome (ARDS).
The term “acute respiratory distress syndrome” was used instead of “adult respiratory distress syndrome” because the syndrome occurs in both adults and children.

5. ARDS was recognized as the most severe form of acute lung injury (ALI), a form of diffuse alveolar injury.
The AECC defined ARDS as an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence for cardiogenic pulmonary edema.
The severity of hypoxemia necessary to make the diagnosis of ARDS was defined by the ratio of the partial pressure of oxygen in the patient’s arterial blood (PaO2) to the fraction of oxygen in the inspired air (FiO2).
ARDS was defined by a PaO2/FiO2 ratio of less than 200, and in ALI, less than 300.

6. This definition was further refined in 2011 by a panel of experts and is termed the Berlin definition of ARDS.
ARDS is defined by timing (within 1 wk of clinical insult or onset of respiratory symptoms); radiographic changes (bilateral opacities not fully explained by effusions, consolidation, or atelectasis); origin of edema (not fully explained by cardiac failure or fluid overload); and severity based on the PaO2/FiO2 ratio on 5 cm of continuous positive airway pressure (CPAP).
The 3 categories are mild (PaO2/FiO ), moderate (PaO2/FiO ), and severe (PaO2/FiO2 ≤100).

7. Pathophysiology

8. 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.

9. 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.

10. 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.

11. Injury to the alveolar lining cells also promotes pulmonary edema formation.
Two types of alveolar epithelial cells exist.
Type I cells, which make up 90% of the alveolar epithelium, are injured easily.
Damage to type I cells allows both increased entry of fluid into the alveoli and decreased clearance of fluid from the alveolar space.

12. Type II alveolar epithelial cells are relatively more resistant to injury.
However, type II cells have several important functions, including the production of surfactant, ion transport, and proliferation and differentiation into type l cells after cellular injury.
Damage to type II cells results in decreased production of surfactant with resultant decreased compliance and alveolar collapse.
Interference with the normal repair processes in the lung may lead to the development of fibrosis.

13. Neutrophils are thought to play a key role in the pathogenesis of ARDS, as suggested by studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS.
Despite the apparent importance of neutrophils in this syndrome, ARDS may develop in profoundly neutropenic patients, and infusion of granulocyte colony-stimulating factor (G-CSF) in patients with ventilator-associated pneumonia (VAP) does not promote its development.
This and other evidence suggests that the neutrophils observed in ARDS may be reactive rather than causative.

14. Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor, and numerous others), along with platelet sequestration and activation, are also important in the development of ARDS.
An imbalance of pro-inflammatory and anti-inflammatory cytokines is thought to occur after an inciting event, such as sepsis.
Evidence from animal studies suggests that the development of ARDS may be promoted by the positive airway pressure delivered to the lung by mechanical ventilation. This is termed ventilator- associated lung injury (VALI).

15. ARDS expresses itself as an inhomogeneous process.
Relatively normal alveoli, which are more compliant than affected alveoli, may become over-distended by the delivered tidal volume, resulting in barotrauma (pneumothorax and interstitial air).
Alveoli already damaged by ARDS may experience further injury from the shear forces exerted by the cycle of collapse at end-expiration and re-expansion by positive pressure at the next inspiration (so-called volutrauma).

16. In addition to the mechanical effects on alveoli, these forces promote the secretion of pro- inflammatory cytokines with resultant worsening inflammation and pulmonary edema.
The use of positive end-expiratory pressure (PEEP) to diminish alveolar collapse and the use of low tidal volumes and limited levels of inspiratory filling pressures appear to be beneficial in diminishing the observed VALI.

17. ARDS causes a marked increase in intrapulmonary shunting, leading to severe hypoxemia.
Although a high FiO2 is required to maintain adequate tissue oxygenation and life, additional measures, like lung recruitment with PEEP, are often required.
Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity.
Generally, oxygen concentrations higher than 65% for prolonged periods (days) can result in DAD, hyaline membrane formation, and, eventually, fibrosis.

18. 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.

19. 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.

20. Etiology

21. Multiple risk factors exist for ARDS.
Approximately 20% of patients with ARDS have no identified risk factor.
ARDS risk factors include direct lung injury (most commonly, aspiration of gastric contents), systemic illnesses, and injuries.
The most common risk factor for ARDS is sepsis.

22. Given the number of adult studies, major risk factors associated with the development of ARDS include the following:
Bacteremia
Drug overdose
Sepsis
Near drowning
Trauma, with or without pulmonary contusion
Postperfusion injury after cardiopulmonary bypass
Fractures, particularly multiple fractures and long bone fractures
Pancreatitis
Fat embolism
Burns
Massive transfusion
Pneumonia
Aspiration

23. 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, [4] and alcohol use. For any underlying cause, increasingly severe illness as predicted by a severity scoring system such as the Acute Physiology And Chronic Health Evaluation (APACHE) increases the risk of development of ARDS.

24. Genetic factors
A study by Glavan et al examined the association between genetic variations in the FAS gene and ALI susceptibility.
The study identified associations between four single nucleotide polymorphisms and increased ALI susceptibility.
Further studies are needed to examine the role of FAS in ALI.

25. Epidemiology

26. The incidence of ARDS varies widely, partly because studies have used different definitions of the disease.
Moreover, to determine an accurate estimate of its incidence, all cases of ARDS in a given population must be found and included.
Although this may be problematic, recent data are available from the United States and international studies that may clarify the true incidence of this condition.

27. United States statistics
In the 1970s, when a National Institutes of Health (NIH) study of ARDS was being planned, the estimated annual frequency was 75 cases per 100,000 population.
Subsequent studies, before the development of the AECC definitions, reported much lower figures. For example, a study from Utah showed an estimated incidence of cases per 100,000 population.

28. A prospective study using the 1994 AECC definition was performed in King County, Washington, from April 1999 through July 2000 and found that the age-adjusted incidence of ALI was 86.2 per 100,000 person-years.
Incidence increased with age, reaching 306 per 100,000 person-years for people in aged years.

29. On the basis of these statistics, it is estimated that 190,600 cases exist in the United States annually and that these cases are associated with 74,500 deaths.

30. International statistics
The first study to use the 1994 AECC definitions was performed in Scandinavia, which reported annual rates of 17.9 cases per 100,000 population for ALI and 13.5 cases per 100,000 population for ARDS.

31. Age-related differences in incidence
ARDS may occur in people of any age.
Its incidence increases with advancing age, ranging from 16 cases per 100,000 person-years in those aged years to 306 cases per 100,000 person- years in those between the ages of 75 and 84 years.
The age distribution reflects the incidence of the underlying causes.

32. Sex-related differences in incidence
For ARDS associated with sepsis and most other causes, no differences in the incidence between males and females appear to exist.
However, in trauma patients only, the incidence of the disease may be slightly higher among females.

33. Prognosis

34. Until the 1990s, most studies reported a 40-70% mortality rate for ARDS.
However, 2 reports in the 1990s, one from a large county hospital in Seattle and one from the United Kingdom, suggested much lower mortality rates, in the range of %.
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.

35. Note that most deaths in ARDS patients are attributable to sepsis (a poor prognostic factor) or multi-organ failure rather than to a primary pulmonary cause, although the recent success of mechanical ventilation using smaller tidal volumes may suggest a role of lung injury as a direct cause of death.

36. Mortality in ARDS increases with advancing age
Mortality in ARDS increases with advancing age. The study performed in King County, Washington, found mortality rates of 24% in patients between ages 15 and 19 years and 60% in patients aged 85 years and older.
The adverse effect of age may be related to underlying health status.

37. Indices of oxygenation and ventilation, including the PaO2/FiO2 ratio, do not predict the outcome or risk of death.
The severity of hypoxemia at the time of diagnosis does not correlate well with survival rates.
However, the failure of pulmonary function to improve in the first week of treatment is a poor prognostic factor.

38. Peripheral blood levels of decoy receptor 3 (DcR3), a soluble protein with immunomodulatory effects, independently predict 28-day mortality in ARDS patients.
In a study comparing DcR3, soluble triggering receptor expressed on myeloid cells (sTREM)-1, TNF-alpha, and IL-6 in ARDS patients, plasma DcR3 levels were the only biomarker to distinguish survivors from non- survivors at all time points in week 1 of ARDS.

39. Non-survivors had higher DcR3 levels than survivors, regardless of APACHE II scores, and mortality was higher in patients with higher DcR3 levels.

40. Morbidity is considerable.
Patients with ARDS are likely to have prolonged hospital courses, and they frequently develop nosocomial infections, especially ventilator-associated pneumonia (VAP).
In addition, patients often have significant weight loss and muscle weakness, and functional impairment may persist for months after hospital discharge.

41. Severe disease and prolonged duration of mechanical ventilation are predictors of persistent abnormalities in pulmonary function.
Survivors of ARDS have significant functional impairment for years following recovery.

42. In a study of 109 survivors of ARDS, 12 patients died in the first year.
In 83 evaluable survivors, spirometry and lung volumes were normal at 6 months, but diffusing capacity remained mildly diminished (72%) at 1 year.

43. ARDS survivors had abnormal 6-minute walking distances at 1 year, and only 49% had returned to work.
Their health-related quality of life was significantly below normal.
However, no patient remained oxygen dependent at 12 months.
Radiographic abnormalities had also completely resolved.

44. A study of this same group of patients 5 years after recovery from ARDS (9 additional patients had died and 64 were evaluated) was recently published and demonstrated continued exercise impairment and decreased quality of life related to both physical and neuropsychological factors.

45. A study examining health-related quality of life (HRQL) after ARDS determined that ARDS survivors had poorer overall HRQL than the general population at 6 months after recovery.
This included lower scores in mobility, energy, and social isolation.

46. Acute Respiratory Distress Syndrome Clinical Presentation

47. History

48. Acute respiratory distress syndrome (ARDS) is characterized by the development of acute dyspnea and hypoxemia within hours to days of an inciting event, such as trauma, sepsis, drug overdose, massive transfusion, acute pancreatitis, or aspiration. In many cases, the inciting event is obvious, but, in others (eg, drug overdose), it may be harder to identify.

49. Patients developing ARDS are critically ill, often with multi-system organ failure, and they may not be capable of providing historical information.
Typically, the illness develops within hours after the inciting event, although, in rare instances, it may take up to a few days.

50. With the onset of lung injury, patients initially note dyspnea with exertion.
This rapidly progresses to severe dyspnea at rest, tachypnea, anxiety, agitation, and the need for increasingly high concentrations of inspired oxygen.

51. Physical Examination

52. Physical findings often are nonspecific and include tachypnea, tachycardia, and the need for a high fraction of inspired oxygen (FiO2) to maintain oxygen saturation.
The patient may be febrile or hypothermic.
Because ARDS often occurs in the context of sepsis, associated hypotension and peripheral vasoconstriction with cold extremities may be present.
Cyanosis of the lips and nail beds may occur.

53. Examination of the lungs may reveal bilateral rales.
Rales may not be present despite widespread involvement.
Because the patient is often intubated and mechanically ventilated, decreased breath sounds over 1 lung may indicate a pneumothorax or endotracheal tube down the right main bronchus.

54. Manifestations of the underlying cause (eg, acute abdominal findings in the case of ARDS caused by pancreatitis) are present.

55. In a septic patient without an obvious source, pay careful attention during the physical examination to identify potential causes of sepsis, including signs of lung consolidation or findings consistent with an acute abdomen.
Carefully examine sites of intravascular lines, surgical wounds, drain sites, and decubitus ulcers for evidence of infection.
Check for subcutaneous air, a manifestation of infection or barotrauma.

56. Because cardiogenic pulmonary edema must be distinguished from ARDS, carefully look for signs of congestive heart failure or intravascular volume overload, including jugular venous distention, cardiac murmurs and gallops, hepatomegaly, and edema.

57. Complications

58. Patients with ARDS often require high-intensity mechanical ventilation, including high levels of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) and, possibly, high mean airway pressures; thus, barotrauma may occur.
Patients present with pneumomediastinum, pneumothorax, or both.
Other potential complications that may occur in these mechanically ventilated patients include accidental extubation and right mainstem intubation.

59. If prolonged mechanical ventilation is needed, patients may eventually require tracheostomy.
With prolonged intubation and tracheostomy, upper airway complications may occur, most notably post- extubation laryngeal edema and subglottic stenosis.

60. Because patients with ARDS often require prolonged mechanical ventilation and invasive hemodynamic monitoring, they are at risk for serious nosocomial infections, including ventilator-associated pneumonia (VAP) and line sepsis.
The incidence of VAP in ARDS patients may be as high as 55% and appears to be higher than that in other populations requiring mechanical ventilation.
Preventive strategies including elevation of head of the bed, use of subglottic suction endotracheal tubes, and oral decontamination.

61. Other potential infections include urinary tract infection (UTI) related to the use of urinary catheters and sinusitis related to the use of nasal feeding and drainage tubes.
Patients may also develop Clostridium difficile colitis as a complication of broad-spectrum antibiotic therapy.
Patients with ARDS, because of the extended intensive care unit (ICU) stay and treatment with multiple antibiotics, may also develop infections with drug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

62. In a study of survivors of ARDS, significant functional impairment was noted at 1 year, primarily related to muscle wasting and weakness.
Corticosteroid treatment and use of neuromuscular blockade are risk factors for muscle weakness and poor functional recovery.

63. 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.

64. 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.

65. 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 (erythropoietin).

66. Acute Respiratory Distress Syndrome Differential Diagnoses

67. Diagnostic Considerations

68. Other conditions to be considered include the following:
Acute hypersensitivity pneumonitis
Transfusion-related acute lung injury (TRALI)
Pulmonary hemorrhage
Near drowning
Acute eosinophilic pneumonia
Drug reaction
Reperfusion injury
Noncardiogenic pulmonary edema
Leukemic infiltration
Fat embolism syndrome
Hamman-Rich syndrome
Retinoic acid syndrome

69. Differential Diagnoses

70. Aspiration Pneumonitis and Pneumonia
Noninvasive Ventilation
Toxic Shock Syndrome
Hospital-Acquired Pneumonia (Nosocomial Pneumonia) and Ventilator-Associated Pneumonia
Transfusion Reactions
Bacterial Pneumonia
Tumor Lysis Syndrome
Bacterial Sepsis
Ventilator-Associated Pneumonia
Goodpasture Syndrome
Perioperative Pulmonary Management
Hemorrhagic Shock
Viral Pneumonia
Heroin Toxicity
Pneumocystis jiroveci Pneumonia
Hypersensitivity Pneumonitis
Pulmonary Eosinophilia
Mechanical Ventilation
Respiratory Failure
Multiple Organ Dysfunction Syndrome in Sepsis
Salicylate Toxicity
Septic Shock

71. Acute Respiratory Distress Syndrome Workup

72. Approach Considerations

73. Acute respiratory distress syndrome (ARDS) is defined by the acute onset of bilateral pulmonary infiltrates and severe hypoxemia in the absence of evidence of cardiogenic pulmonary edema.
Workup includes selected laboratory tests, diagnostic imaging, hemodynamic monitoring, and bronchoscopy.
ARDS is a clinical diagnosis, and no specific laboratory abnormalities are noted beyond the expected disturbances in gas exchange and radiographic findings.

74. Laboratory Tests

75. In ARDS, if the partial pressure of oxygen in the patient’s arterial blood (PaO2) is divided by the fraction of oxygen in the inspired air (FiO2), the result is 300 or less.
For patients breathing 100% oxygen, this means that the PaO2 is less than 300.

76. 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.

77. 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.

78. To exclude cardiogenic pulmonary edema, it may be helpful to obtain a plasma B-type natriuretic peptide (BNP) value and echocardiogram. A BNP level of less than 100 pg/mL in a patient with bilateral infiltrates and hypoxemia favors the diagnosis of ARDS/acute lung injury (ALI) rather than cardiogenic pulmonary edema.
The echocardiogram provides information about left ventricular ejection fraction, wall motion, and valvular abnormalities.

79. Other abnormalities observed in ARDS depend on the underlying cause or associated complications and may include the following:

80. 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.

81. Renal:
Acute tubular necrosis (ATN) often ensues in the course of ARDS, probably from ischemia to the kidneys.
Renal function should be closely monitored.

82. Hepatic:
Liver function abnormalities may be noted in either a pattern of hepatocellular injury or cholestasis.

83. Cytokines:
Multiple cytokines, such as interleukin (IL)–1, IL-6, and IL-8, are elevated in the serum of patients at risk for ARDS.

84. Radiography

85. 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.

86. The pulmonary infiltrates usually evolve rapidly, with maximal severity within the first 3 days.
Infiltrates can be noted on chest radiographs almost immediately after the onset of gas exchange abnormalities.
They may be interstitial, characterized by alveolar filling, or both.

87. Initially, the infiltrates may have a patchy peripheral distribution, but soon they progress to diffuse bilateral involvement with ground glass changes or frank alveolar infiltrates (see the image below).

88. Anteroposterior portable chest radiograph in patient who had been in respiratory failure for 1 week with diagnosis of acute respiratory distress syndrome. Image shows endotracheal tube, left subclavian central venous catheter in superior vena cava, and bilateral patchy opacities in mostly middle and lower lung zones.

89. The correlation between radiographic findings and severity of hypoxemia is highly variable.
In addition, diuresis tends to improve infiltrates and volume overload tends to worsen them, irrespective of improvement or worsening in underlying ARDS.

90. For patients who begin to improve and show signs of resolution, improvement in radiographic abnormalities generally occurs over days; however, more protracted courses are common.

91. Computed Tomography

92. In general, clinical evaluation and routine chest radiography are sufficient in patients with ARDS.
However, computed tomography (CT) scanning may be indicated in some situations.
CT scanning is more sensitive than plain chest radiography in detecting pulmonary interstitial emphysema, pneumothoraces and pneumomediastinum, pleural effusions, cavitation, and mediastinal lymphadenopathy.
The heterogeneity of alveolar involvement is often apparent on CT scan even in the presence of diffuse homogeneous infiltrates on routine chest radiograph.

93. 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 (ICU) to the CT scan equipment.

94. Echocardiography

95. As part of the workup, patients with ARDS should undergo 2-dimensional echocardiography for the purpose of screening.
If findings are suggestive of patent foramen ovale shunting, 2-dimensional echocardiography should be followed up with transesophageal echocardiography.

96. Because patients with severe ARDS often require prolonged prone positioning due to refractory hypoxemia, a study assessed the use of transesophageal echocardiography (TEE) in patients in the prone position.
The study determined that TEE can be safely and efficiently performed in patients with severe ARDS in the prone position.

97. Invasive Hemodynamic Monitoring

98. Because avoiding fluid-overload may be beneficial in the management of ARDS, the use of a central venous catheter or pulmonary artery 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.

99. Use of the generic pulmonary artery catheter past the time of initial resuscitation confers no survival benefit and possibly has an adverse effect on survival.

100. In addition, accurate measurement of hemodynamic parameters with the pulmonary artery 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.

101. Bronchoscopy

102. Bronchoscopy may be considered to evaluate the possibility of infection, alveolar hemorrhage, or acute eosinophilic pneumonia in patients acutely ill with bilateral pulmonary infiltrates.
Culture material may be obtained by wedging the bronchoscope in a sub-segmental bronchus and collecting the fluid suctioned after instilling large volumes of non- bacteriostatic saline (bronchoalveolar lavage; BAL).
The fluid is analyzed for cell differential, cytology, silver stain, and Gram stain and is quantitatively cultured.

103. Ten thousand organisms per milliliter is generally considered significant in a patient not previously treated with antibiotics.
As noted, 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.

104. 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 non-bacteriostatic saline. Culture of 1000 organisms is considered significant.

105. 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.

106. 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.

107. 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.

108. The use of bronchoscopy as an adjunct to surfactant therapy has been reported.
In 10 adults with ARDS, sequential bronchopulmonary segmental lavage with a dilute synthetic was safe, well tolerated, and associated with a decrease in oxygen requirements.
To the authors’ knowledge, no study has been performed to compare the use of surfactant with or without bronchoscopy in the setting of ARDS.

109. Histologic Findings

110. 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.

111. Photomicrograph from patient with acute respiratory distress syndrome (ARDS). Image shows ARDS in exudative stage. Note hyaline membranes and loss of alveolar epithelium in this early stage of ARDS.

112. 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 of fibroblasts, myofibroblasts, and collagen deposition in the interstitium.

113. The final phase of ARDS is fibrotic
The final phase of ARDS is fibrotic. Alveolar walls are thickened by connective tissue rather than edema or cellular infiltrate.

114. Acute Respiratory Distress Syndrome Treatment & Management

115. Approach Considerations

116. No drug has proved beneficial in the prevention or management of acute respiratory distress syndrome (ARDS).
Early administration of corticosteroids to septic patients does not prevent the development of ARDS.

117. Numerous pharmacologic therapies, including the use of inhaled synthetic surfactant, intravenous (IV) antibody to endotoxin, ketoconazole, simvastatin, and ibuprofen, have been tried and are not effective.

118. A study that examined the use and outcomes associated with rescue therapies in patients with ARDS determined that these therapies offered no survival benefit.
The study also determined that rescue therapies are most often used in younger patients with more severe oxygenation deficits.

119. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, seemed promising in early trials, but in larger controlled trials, it did not change mortality rates in adults with ARDS.
A systematic review, meta-analysis, and trial sequential analysis of 14 randomized controlled trials, including 1303 patients, found that inhaled nitric oxide did not reduce mortality and results in only a transient improvement in oxygenation.

120. Although no specific therapy exists for ARDS, treatment of the underlying condition is essential, along with supportive care, noninvasive ventilation or mechanical ventilation using low tidal volumes, and conservative fluid management.

121. Because infection is often the underlying cause of ARDS, early administration of appropriate antibiotic therapy broad enough to cover suspected pathogens is essential, along with careful assessment of the patient to determine potential infection sources.
In some instances, removal of intravascular lines, drainage of infected fluid collections, or surgical debridement or resection of an infected site (eg, the ischemic bowel) may be necessary because sepsis-associated ARDS does not resolve without such management.

122. In addition, preventing complications associated with prolonged mechanical ventilation and ICU stay can include deep venous thrombosis (DVT) prophylaxis, stress ulcer prophylaxis, early mobilization, minimizing sedation, turning and skin care, and strategies to prevent ventilator-induced pneumonia, such as elevation of the head of the bed and use of a subglottic suction device.

123. The only treatment found to improve survival in ARDS is a mechanical ventilation strategy using low tidal volumes (6 mL/kg based upon ideal body weight).

124. The main concerns are missing a potentially treatable underlying cause or complication of ARDS.
In these critically ill patients, pay careful attention to early recognition of potential complications in the intensive care unit (ICU), including pneumothorax, IV line infections, skin breakdown, inadequate nutrition, arterial occlusion at the site of intra-arterial monitoring devices, DVT and pulmonary embolism (PE), retroperitoneal hemorrhage, gastrointestinal (GI) hemorrhage, erroneous placement of lines and tubes, and the development of muscle weakness.

125. In situations where 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.

126. As in all situations in which patients are critically ill, family and friends are under stress and likely have many questions and concerns.
Keep them informed and allow them to be at the bedside as much as possible.
Caretakers should assume that even though sedated, the patient may be capable of hearing and understanding all conversations in the room and may experience pain.
Keeping this in mind, all conversation at the bedside should be appropriate and all procedures should be performed with local anesthesia and pain medication.

127. Fluid Management

128. Distinguishing between initial fluid resuscitation, as used for therapy of septic shock, and maintenance fluid therapy is important.
Early aggressive resuscitation for associated circulatory shock and its associated remote organ injury are central aspects of initial management.

129. However, 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.
Thus, distinction between primary ARDS due to aspiration, pneumonia, or inhalational injury, which usually can be treated with fluid restriction, from secondary ARDS due to remote infection or inflammation that requires initial fluid and potential vasoactive drug therapy is central in directing initial treatments to stabilize the patient.

130. The use of a conservative fluid management approach has been called into question by the long-term followup of a subset of survivors of the Fluid and Catheter Treatment Trial (FACTT). Although mortality in the survivors was similar regardless of fluid management strategy, and the conservative fluid management group required about 18 hours less mechanical ventilatory support, cognitive function was markedly impaired in the conservative fluid group compared with the liberal fluid group, with an adjusted odds ratio of 3.35.

131. Cognitive impairment was defined as impairment in memory, verbal fluency, or executive function. Although all those were more common in the conservative fluid management group, only the decrement in executive function reached statistical significance (p=0.001).
Lower partial pressure of arterial oxygen during the trial was also independently associated with cognitive impairment.

132. Maintaining a low-normal intravascular volume may be facilitated by hemodynamic monitoring with a central venous or pulmonary artery (Swan-Ganz) catheter, aimed at achieving a central venous pressure (CVP) or pulmonary capillary wedge pressure (PCWP) at the lower end of normal.
The ARDS clinical trials network of pulmonary artery catheter versus CVP to guide fluid management in ARDS showed no difference in mortality or ventilator-free days, regardless of whether fluid status was monitored by pulmonary artery catheter or CVP.

133. 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.

134. A study by Lakhal et al determined that respiratory pulse pressure variation fails to predict fluid responsiveness in patients with ARDS.
Careful fluid challenges may be a safer alternative.

135. Noninvasive Ventilation and High-Flow Nasal Cannula

136. Because intubation and mechanical ventilation may be associated with an increased incidence of complications, such as barotrauma and nosocomial pneumonia, alternatives to mechanical ventilation such as a high-flow nasal cannula or noninvasive positive-pressure ventilation (NIPPV) may be beneficial in patients with ARDS.

137. High-flow nasal cannula uses a system of heated humidification and large-bore nasal prongs to deliver oxygen at flows of up to 50 L/min.
This is usually used in conjunction with an oxygen blender, allowing delivery of precise inspired oxygen concentrations.
High-flow nasal cannula is usually well tolerated and allows the patient to talk, eat, and move around.
NIPPV is usually given by full face-mask.

138. Sometimes, continuous positive airway pressure (CPAP) alone may be sufficient to improve oxygenation.
In a 2015 study on hypoxemic, non-hypercapnic patients comparing standard oxygen, high-flow nasal cannula, and NIPPV, all three modes had the same incidence of need for intubation/mechanical ventilation, but high-flow nasal cannula resulted in improved 90-day mortality.

141. Noninvasive ventilation has been studied best in patients with hypercapnic respiratory failure caused by chronic obstructive pulmonary disease (COPD) or neuromuscular weakness.

142. Patients who have a diminished level of consciousness, vomiting, upper GI bleeding, or other conditions that increase aspiration risk are not candidates for NIPPV.
Other relative contraindications include hemodynamic instability, agitation, and inability to obtain good mask fit.

143. Mechanical Ventilation

144. The goals of mechanical ventilation in ARDS are to maintain oxygenation while avoiding oxygen toxicity and the complications of mechanical ventilation.
Generally, this involves maintaining oxygen saturation in the range of 85-90%, with the aim of reducing the fraction of inspired oxygen (FiO2) to less than 65% within the first hours.
Achieving this aim almost always necessitates the use of moderate-to-high levels of positive end-expiratory pressure (PEEP).

145. Experimental studies have shown that mechanical ventilation may promote a type of acute lung injury termed ventilator-associated lung injury.
A protective ventilation strategy using low tidal volumes and limited plateau pressures improves survival when compared with conventional tidal volumes and pressures.

146. In an ARDS Network study, patients with ALI and ARDS were randomized to mechanical ventilation either at a tidal volume of 12 mL/kg of predicted body weight and an inspiratory pressure of 50 cm water or less or at a tidal volume of 6 mL/kg and an inspiratory pressure of 30 cm water 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%).

147. Whereas 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 as compared with earlier studies that had failed to demonstrate a benefit.

148. 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 water or less.
Increase the ventilator rate and administer bicarbonate as needed to maintain the pH at a near normal level (7.3).

149. In the ARDS Network study, patients ventilated with lower tidal volumes required higher levels of PEEP (9.4 vs 8.6 cm water) 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 Network trial of higher versus lower PEEP levels in patients with ARDS showed no benefit from higher PEEP levels in terms of either survival or duration of mechanical ventilation.

150. Patients with severe ARDS receiving mechanical ventilation responded more favorably to early administration of a neuromuscular blocking agent (ie, cisatracurium) than to placebo.
Compared with the placebo group, the cisatracurium group showed improvement in 90-day survival and increased time off the ventilator.
No significant difference in ICU-acquired paresis was observed.

151. Managing physicians should not use paralytics in all cases; rather, they should use them only in those where length of ventilation is expected to exceed a few hours.
Patients should not remain ventilated for longer than it takes for the paralytics to have their effect.
The duration of paralysis will depend upon the condition.

152. A study by Jaber et al examined diaphragmatic weakness during mechanical ventilation along with the relationship between mechanical ventilation duration and diaphragmatic injury or atrophy.
The study determined that longer periods of mechanical ventilation were associated with significantly greater ultrastructural fiber injury, increased ubiquitinated proteins, higher expression of p65 nuclear factor-kB, greater levels of calcium-activated proteases, and decreased cross-sectional area of muscle fibers in the diaphragm.

153. The conclusion was that weakness, injury, and atrophy can occur rapidly in the diaphragms of patients on mechanical ventilation and are significantly correlated with the duration of ventilator support.

154. Positive end-expiratory pressure and continuous positive airway pressure

155. 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 the FiO2 to be tapered.

156. 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.

157. 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.

158. 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%.

159. Another approach, favored by Amato et al, 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 water.

160. However, as noted above, an ARDS Network study of higher versus lower PEEP levels in ARDS patients did not find higher PEEP levels advantageous.
In this study, PEEP level was determined by how much inspired oxygen was required to achieve a goal oxygen saturation of 88-95% or a target partial pressure of oxygen (PO2) of 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.

161. Pressure-controlled ventilation and high-frequency ventilation

162. 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).

163. 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 7:1 have been used.
PCV, using lower peak pressures, may also be beneficial in patients with bronchopleural fistulae, facilitating closure of the fistula.

164. Evidence indicates that PCV may be beneficial in ARDS, even without the special circumstances noted.
In a multicenter controlled trial comparing VCV with PCV in ARDS patients, 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.

165. High-frequency ventilation (jet or oscillatory) is a ventilator mode that uses low tidal volumes and high respiratory rates.
Given that distention of alveoli is known to one of the mechanisms promoting ventilator-associated lung injury, high-frequency ventilation would be expected to be beneficial in ARDS.
Results of clinical trials comparing this approach with conventional ventilation in adults have generally demonstrated early improvement in oxygenation but no improvement in survival.
HFOV may be the most useful for patients with bronchopleural fistulae.

166. Partial liquid ventilation has also been tried in ARDS.
A randomized controlled trial that compared it with conventional mechanical ventilation determined that partial liquid ventilation resulted in increased morbidity (pneumothoraces, hypotension, and hypoxemic episodes), and a trend toward higher mortality.

167. Prone positioning

168. Some 60-75% 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 substantial 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.

169. 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.

170. Despite improved oxygenation with the prone position, randomized controlled trials of the prone position in ARDS have not demonstrated improved survival.
However, a subsequent French study, in which patients were in the prone position for at least 8 hours per day, did not document a benefit from the prone position in terms of 28-day or 90-day mortality, duration of mechanical ventilation, or development of ventilator- associated pneumonia (VAP).

171. Tracheostomy

172. In patients requiring prolonged mechanical ventilation, tracheostomy allows the establishment of a more stable airway, which may allow for mobilization of the patient and, in some instances, may facilitate weaning from mechanical ventilation.
Tracheostomy, may be performed in the operating room or percutaneously at the bedside.
Timing of the procedure should be individualized, but it is generally performed after about 2 weeks of mechanical ventilation.

173. Extracorporeal Membrane Oxygenation

174. A large multi-center trial in the 1970s demonstrated that extracorporeal membrane oxygenation (ECMO) did not improve the mortality rate in ARDS patients.
A later trial using extracorporeal carbon dioxide removal along with inverse ratio ventilation also did not improve survival in ARDS.
However, ECMO is still used as a rescue therapy in selected cases.
During the H1N1 epidemic in 2009, ECMO appeared to improve survival in patients with H1N1-associated ARDS who could not be oxygenated with conventional mechanical ventilation.

175. Nutritional Support

176. Institution of nutritional support after hours of mechanical ventilation usually is recommended. Enteral nutrition via a feeding tube is preferable to IV hyperalimentation unless it is contraindicated because of an acute abdomen, ileus, GI bleeding, or other conditions.

177. A low-carbohydrate high-fat enteral formula including anti- inflammatory and vasodilating components (eicosapentaenoic acid and linoleic acid) along with antioxidants has been demonstrated in some studies to improve outcome in ARDS.
In a prospective, randomized study of ARDS patients in Brazil given an enteral formula containing antioxidants, eicosapentaenoic acid, and gamma-linoleic acid compared with a standard isocaloric formula, Pontes-Arruda demonstrated improved survival and oxygenation with the specialized diet.

178. The ARDSNet completed a trial of feeding in ARDS (the EDEN-OMEGA study), in which patients were randomized to supplements containing omega-3 fatty acid and antioxidants versus placebo. This study was terminated early for futility, but the full results have not yet been published.

179. An open-label, multicenter trial (the EDEN study) randomized 1000 adult patients who required mechanical ventilation within 48 hours of developing acute lung injury to receive either trophic or full enteral feeding for the first 6 days. Initial lower- volume trophic enteral feeding did not improve ventilator-free days, 60-day mortality, or infectious complications compared with initial full enteral feeding, but it was associated with less gastrointestinal intolerance.

180. Activity Restriction

181. Patients with ARDS are on bed rest
Patients with ARDS are on bed rest. Frequent position changes should be started immediately, as should passive—and, if possible, active—range-of-motion activities of all muscle groups. Elevation of the head of the bed to a 45° angle is recommended to diminish the development of VAP.
Recently, increased interest in minimizing sedation and earlier ambulation has been proposed. Such approaches are associated with less posttraumatic stress disorder in survivors and was the preferred approach by patients’ families. If at all possible, use of minimal sedation, sedation holidays, and more ambulation appear to be the goals of management once severe cardiovascular insufficiency, if present, has resolved.

182. Transfer Considerations

183. Once the acute phase of ARDS resolves, patients may require a prolonged period to be weaned 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.

184. Transfer of the ARDS patient to a tertiary care facility may be indicated in some situations, provided that safe transport can be arranged. Transfer may be indicated if the FIO2 cannot be lowered to less than 0.65 within 48 hours.

185. 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.

186. 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.

187. Prevention

188. Although multiple risk factors for ARDS are known, no successful preventive measures have 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 (eg, elevating the head of the bed and evaluating swallowing mechanics before feeding high- risk patients) may also prevent some ARDS cases.

189. In patients without ARDS on mechanical ventilation, the use of high tidal volumes appears to be a risk factor for the development of ARDS, and, therefore, the use of lower tidal volumes in all patients on mechanical ventilation may prevent some cases on ARDS.

190. Acute Respiratory Distress Syndrome Medication

191. Medication Summary

192. No drug has proved beneficial in the prevention or management of acute respiratory distress syndrome (ARDS).
Early administration of corticosteroids to septic patients does not prevent the development of ARDS. Numerous pharmacologic therapies, including the use of inhaled or instilled synthetic surfactant, intravenous (IV) antibody to endotoxin, ketoconazole, and ibuprofen, have been tried and are not effective. Statins, which also appeared to have promise in small studies, also did not show benefit in a recently published randomized trial in 60 patients with acute lung injury (ALI).

193. Small sepsis trials suggest a potential role for antibody to tumor necrosis factor (TNF) and recombinant interleukin (IL)–1 receptor antagonist.
Inhaled nitric oxide (NO), a potent pulmonary vasodilator, seemed promising in early trials, but in larger controlled trials, it did not change mortality rates in adults with ARDS.
Inhaled prostacyclin also has not been shown to improve survival.

194. Because of apparent benefit in small trials, it was thought that there might be a role for high-dose corticosteroid therapy in patients with late (fibroproliferative phase) ARDS.
However, an ARDS Study Network trial of methylprednisolone for patients with ARDS persisting for at least 7 days demonstrated no benefit in terms of 60-day mortality.
Patients treated later in the course of ARDS, 14 days after onset, had worsened mortality with corticosteroid therapy.

195. 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.

196. Corticosteroids

197. 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 who have had ARDS for >14 d).

198. 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 bronchoalveolar lavage (BAL) and quantitative culture.