ARDS


Acute Respiratory Distress Syndrome

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The following is a compilation of various related entries about ARDS taken from a variety of sites including but not limited to the ARDSNet, Medscape, Pubmed, PubmedHealth UpToDate.com, Wikipedia website.

INTRODUCTION

A distinct type of hypoxemic respiratory failure characterized by acute abnormality of both lungs was first recognized during the 1960s.

The Berlin Definition of ARDS (published in 2012) has replaced the American-European Consensus Conference’s definition of ARDS (published in 1994) [1,2]. However, it should be recognized that most evidence is based upon prior definitions. The current diagnostic criteria for ARDS are provided separately.

EPIDEMIOLOGY

The incidence of ARDS was determined in a multicenter, population-based, prospective cohort study in the United States [3]. The study followed 1113 patients with ARDS for 15 months beginning in 1999 or 2000:

  • The age-adjusted incidence was 86 per 100,000 person-years for individuals with an arterial oxygen tension to fraction of inspired oxygen ratio (PaO2/FiO2) ≤300 mmHg and 64 per 100,000 person-years for individuals with a PaO2/FiO2 ≤200 mmHg.
  • The incidence increased with patient age from 16 per 100,000 person-years among individuals 15 to 19 years of age to 306 per 100,000 person-years among individuals 75 to 84 years of age.
  • Extrapolation of the data suggested that there are approximately 190,000 cases of ARDS in the United States each year [3].

Within ICUs, approximately 10 to 15 percent of admitted patients and up to 20 percent of mechanically ventilated patients meet criteria for ARDS [4-7]. The incidence of ARDS may be somewhat higher in the United States than in other countries [8].

The incidence of ARDS may be decreasing. A prospective cohort study from a single institution reported that the incidence of ARDS decreased from 82.4 cases per 100,000 person-years in 2001 to 38.9 cases per 100,000 person-years in 2008 [9]. This was attributable to a decline in hospital-acquired ARDS, since the incidence of ARDS at hospital presentation did not change. Those who developed ARDS had more severe disease, more comorbidities, and more predisposing conditions. These findings may reflect changes in the delivery of care at this institution only; therefore, studies from other institutions are needed to conclude that the incidence of ARDS is declining in the general population.

PATHOPHYSIOLOGY

Normal lung function requires dry, patent alveoli closely situated to appropriately perfused capillaries, in order to regulate and maintain the movement of a small amount of interstitial fluid around the alveoli. The selectively permeable capillaries allow fluid to cross the membranes under the control of hydrostatic and oncotic forces, while serum proteins remain intravascular. [10]. However, if this process is interrupted through something like lung injury, it can cause an excess of fluid to build up in both the interstitium and alveoli, and therefore, leading to impaired gas exchange, decreased lung compliance, and increased pulmonary arterial pressure.

A simplified version of the Starling equation show below describes the forces directing the fluid movement between the vessels and the interstitium [11].

Q = K x [(Pmv – Ppmv) – rc (πmv – πpmv)]

  1. Q represents the net transvascular flow of fluid,
  2. K the permeability of the endothelial membrane,
  3. Pmv the hydrostatic pressure within the lumen of the microvessels,
  4. Ppmv the hydrostatic pressure in the perimicrovascular space,
  5. rc represents the reflection coefficient of the capillary barrier,
  6. πmv the oncotic pressure in the circulation, and
  7. πpmv the oncotic pressure in the perimicrovascular compartment.

Normally, the hydrostatic and oncotic forces only allow a small amount of fluid into the interstitium, with the following three mechanisms helping prevent alveolar edema [11]:

  1. Retained intravascular protein maintains an oncotic gradient favoring reabsorption
  2. The interstitial lymphatics can return large quantities of fluid to the circulation
  3. Tight junctions between alveolar epithelial cells prevent leakage into the air spaces

Injury

ARDS is a consequence of an alveolar injury producing diffuse alveolar damage [12]. The injury causes release of pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-8 [14-18]. These cytokines recruit neutrophils to the lungs, where they become activated and release toxic mediators (e.g. reactive oxygen species and proteases) that damage the capillary endothelium and alveolar epithelium [12,19-23].

When damage occurs in the capillary endothelium and alveolar epithelium proteins then escape filling the extravascular space. This disrupts the oncotic gradient favoring resorption of fluid causing fluid to be lost and pours into the interstitium. This excess fluid then overwhelms the lymphatics [24], diminishing and ultimately losing their ability to upregulate the excess alveolar fluid [25]. The resulting air spaces then fill with bloody, proteinaceous edema fluid and debris from degenerating cells. In addition, losing valuable functional surfactant and decreasing lung compliance, resulting in alveolar collapse.

Therefore, lung injury has three main consequences including impaired gas exchange, decreased lung compliance, and increased pulmonary arterial pressure.

  1. Impaired gas exchange – Impaired gas exchange in ARDS is primarily due to ventilation-perfusion [V/Q] mismatching: physiologic shunting causes hypoxemia, while increased physiologic dead space impairs carbon dioxide elimination [26,27]. A high minute volume is generally needed to maintain a normal arterial carbon dioxide tension (PaCO2), although hypercapnia is uncommon.
  2. Decreased lung compliance – Decreased pulmonary compliance is one of the hallmarks of ARDS [28]. It is a consequence of the stiffness of poorly or non-aerated lung, rather than the pressure-volume characteristics of residual functioning lung units [29]. Even small tidal volumes can exceed the lung’s inspiratory capacity and cause a dramatic rise in airway pressures [28].
  3. Pulmonary hypertension – Pulmonary hypertension (PH) occurs in up to 25 percent of patients with ARDS who undergo mechanical ventilation [30-32]. Causes include hypoxic vasoconstriction, vascular compression by positive airway pressure, parenchymal destruction, airway collapse, hypercarbia, and pulmonary vasoconstrictors [33]. The clinical importance of PH in most patients with ARDS is uncertain. PH severe enough to cor pulmonale is rare, but it is associated with an increased risk of death [34,35].

Increased airways resistance (Raw) is also a feature of ARDS, although its clinical significance is uncertain [36,37].

PATHOLOGIC STAGES

Patients with ARDS tend to progress through three relatively discrete pathologic stages [38].

  1. The initial stage is the exudative stage, characterized by diffuse alveolar damage.
  2. After approximately seven to ten days, a proliferative stage develops, characterized by resolution of pulmonary edema, proliferation of type II alveolar cells, squamous metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen.
  3. Some patients progress to a fibrotic stage, characterized by obliteration of normal lung architecture, diffuse fibrosis, and cyst formation.

ETIOLOGIES AND PREDISPOSING FACTORS

ARDS has traditionally been conceptualized as a pattern of lung injury and clinical manifestations caused by a variety of insults. However, the validity of the assumption that different inciting events cause a similar pattern of lung injury and similar clinical features has been questioned because numerous studies have found more severe reductions in lung compliance and less responsiveness to positive end-expiratory pressure (PEEP) when the ARDS was due to a pulmonary process than when it was due to an extrapulmonary precipitant, such as sepsis [39-42].

More than 60 possible causes of ARDS have been identified and other potential causes continue to emerge as adverse pulmonary reactions to new therapies are observed. However, only a few common causes account for most cases of ARDS [7,43-46]. Factors that may predispose a patient to develop ARDS, but probably can’t cause ARDS, have also been identified.

  1. SepsisSepsis is the most common cause of ARDS [43,44,47,48]. It should be considered whenever ARDS develops in a patient who is predisposed to serious infection or in association with a new fever or hypotension. The risk of developing ARDS is particularly high among septic patients especially those with a history of alcoholism [49-51]. This was illustrated in a prospective cohort study that determined the incidence of ARDS in 220 patients with septic shock [50]. The incidence of ARDS among patients who chronically abuse alcohol was 70 percent, compared to 31 percent among patients who did not chronically abuse alcohol. A possible explanation for these findings is that alcoholism may decrease the concentration of glutathione in the epithelial lining fluid, predisposing the lung to oxidative injury [49,52,53]. Alternatively, chronic alcohol abuse may increase the risk of ARDS by enhancing inappropriate leukocyte adhesion to endothelial cells [54].
  2. Aspiration — Observational evidence indicates that ARDS will develop in approximately one-third of hospitalized patients who have a recognized episode of aspiration of gastric contents [43,45,55]. It was initially suggested that aspirated contents had to have a pH less than 2.5 to cause severe lung injury [56]; however, more recent animal studies have shown that aspiration of non-acidic gastric contents can also cause widespread damage to the lungs [57]. This suggests that gastric enzymes and small food particles also contribute to the lung injury. The unexpected development of ARDS may be the only indication that an intubated patient has developed a tracheoesophageal fistula. This is a rare complication of intubation.
  3. PneumoniaCommunity acquired pneumonia is probably the most common cause of ARDS that develops outside of the hospital [58]. Common pathogens include Streptococcus pneumoniae [59], Legionella pneumophila, Pneumocystis jirovecii (formerly called Pneumocystis carinii), Staphylococcus aureus, enteric gram negative organisms, and a variety of respiratory viruses [60,61].
  4. Nosocomial pneumonias can also progress to ARDS. Staphylococcus aureus, Pseudomonas aeruginosa, and other enteric gram negative bacteria are the most commonly implicated pathogens.
  5. Severe trauma — ARDS is a complication of severe trauma. There are several situations during which ARDS seems to be particularly common following trauma [62]:
  6. Bilateral lung contusion following blunt trauma [63].
  7. Fat embolism (Fat embolism) after long bone fractures. In this situation, ARDS typically appears 12 to 48 hours after the trauma. This complication has decreased since immobilization for transport to the hospital became routine [65].
  8. Sepsis may be the most common cause of ARDS that develops several days or more after severe trauma or burns.
  9. Massive traumatic tissue injury may directly precipitate or predispose a patient to ARDS [62,65].

Although ARDS can contribute to the length of critical illness following severe trauma, it does not appear to independently increase the risk of death [66]. Trauma-related ARDS has a significantly better prognosis than ARDS that is not related to trauma [67].

  1. Massive transfusion — Transfusion of more than 15 units of red blood cells is a risk factor for the development of ARDS [44]. It is unknown whether the transfusion injures the lungs or the need for massive transfusion identifies patients who are at high risk for ARDS from other causes [68]. Transfusion of smaller volumes of packed red blood cells may also increase the risk of developing ARDS, as well as increasing the risk of mortality among patients with established ARDS [69].
    1. Transfusion-related acute lung injury — Transfusion of even one unit of a plasma-containing blood product sometimes causes ARDS [70,71]. Fresh frozen plasma, platelet, and packed red blood cell transfusions have all been implicated. By definition, respiratory distress becomes apparent within six hours of completion of the transfusion. The mechanism is incompletely understood and may be multifactorial. Lung and hematopoietic stem cell transplantation — During the first two or three days after surgery, lung transplant recipients are prone to primary graft failure. This devastating form of ARDS is attributed to imperfect preservation of the transplanted lung.

Hematopoietic stem cell transplant (hematopoietic stem cell transplant) patients are at risk for ARDS due to a variety of infectious and noninfectious causes. Noninfectious insults include idiopathic pneumonia syndrome, engraftment syndrome, and diffuse alveolar hemorrhage [72]. The lung injury appears to be partly related to the inflammation associated with chemoradiation conditioning regimens, as well as T cell alloreactivity.

  1. Drugs and alcohol — ARDS can occur following an overdose. Drugs that have been implicated include aspirin, cocaine, opioids, phenothiazines, and tricyclic antidepressants [73,74]. Idiosyncratic reactions to other drugs (e.g. protamine, nitrofurantoin), including certain chemotherapeutic agents, occasionally precipitate ARDS after therapeutic doses. Radiologic contrast media can also provoke ARDS in susceptible individuals [75]. Alcohol abuse increases the risk of ARDS due to other causes (e.g. sepsis, trauma), but does not directly cause ARDS [76].
  2. Genetic determinants — It seems likely that there are genetic determinants that increase an individual’s risk of developing ARDS, since only a small proportion of the patients who are exposed to typical insults actually develop ARDS [77]. Studies that link mutations in the surfactant protein B (SP-B) gene to an increased risk of ARDS support this notion [78,79]. Insertion-deletion polymorphisms associated with the angiotensin converting enzyme (ACE) gene have also been suggested as a possible risk factor for ARDS [80], although not all studies support this observation [81].
  3. Other risk factors — Other possible risk factors for ARDS include cigarette smoking [82,83], cardiopulmonary bypass [84,85], pneumonectomy [86], acute pancreatitis [87], obesity [88,89], and near drowning [55,90,91].

Venous air embolism can occasionally cause ARDS. Outside of the operating room, the most common portal of entry for the air is a central venous catheter left open to the air [92].

Lung injury prediction score

The lung injury prediction score (LIPS, LIPS2) identifies patients who are unlikely to develop ARDS. This was demonstrated by a prospective cohort study of 5584 patients, in which seven percent of the cohort developed ARDS, resulting in a negative predictive value (ie, the percent of patients with a LIPS <4 who will not develop ARDS) of 97 percent [93]. A LIPS >4 predicted ARDS with a sensitivity and specificity of 69 and 78 percent, respectively. A smaller study, using a retrospective derivation and prospective validation cohorts reported similar results [94].

The LIPS is the sum of the points assigned for each of the following predisposing conditions:

  1. shock (2 points),
  2. aspiration (2 points),
  3. sepsis (1 point),
  4. pneumonia (1.5 points),
  5. orthopedic spine surgery (1.5 points),
  6. acute abdominal surgery (2 points),
  7. cardiac surgery (2.5 points),
  8. aortic vascular surgery (3.5 points),
  9. traumatic brain injury (2 points),
  10. smoke inhalation (2 points),
  11. near drowning (2 points),
  12. lung contusion (1.5 points),
  13. multiple fractures (1.5 points),
  14. alcohol abuse (1 point),
  15. obesity (BMI >30, 1 point),
  16. hypoalbuminemia (1 point),
  17. chemotherapy (1 point),
  18. fraction of inspired oxygen >0.35 or >4 L/min (2 points),
  19. tachypnea >30 breaths/min (1.5 points),
  20. oxyhemoglobin saturation <95 percent (1 point),
  21. acidosis (pH <7.35, 1.5 points), and
  22. diabetes mellitus (-1 point).

Acute respiratory distress syndrome: Clinical features and diagnosis

CLINICAL FEATURES

The clinical features of ARDS usually appear within 6 to 72 hours of an inciting event and worsen rapidly [44]. Patients typically present with dyspnea, cyanosis (i.e. hypoxemia), and diffuse crackles. Respiratory distress is usually evident, including tachypnea, tachycardia, diaphoresis, and use of accessory muscles of respiration. A cough and chest pain may also exist.

Arterial blood gases reveal hypoxemia, which is often accompanied by acute respiratory alkalosis and an elevated alveolar-arterial oxygen gradient (calculator 1). High concentrations of supplemental oxygen are generally required to maintain adequate oxygenation.

The initial chest radiograph typically has bilateral alveolar infiltrates (picture 1), while computed tomography (CT) usually reveals widespread patchy or coalescent airspace opacities that are usually more apparent in the dependent lung zones (picture 2) [95-97]. The infiltrates do not have to be diffuse or severe, as bilateral infiltrates of any severity are sufficient [98].

Clinical findings related to the precipitant may also exist at presentation. As an example, in patients with ARDS due to sepsis, there may be fever, hypotension, leukocytosis, lactic acidosis, and disseminated intravascular coagulation (DIC).

Clinical course

The first several days of ARDS are characterized by hypoxemia requiring a moderate to high concentration of inspired oxygen. The bilateral alveolar infiltrates and diffuse crackles are persistent during this period and patients may be tenuous due to severe hypoxemia.

Most patients who survive this initial course begin to exhibit better oxygenation and decreasing alveolar infiltrates over the next several days. This may permit the amount of ventilatory support to be decreased and weaning to begin.

Some patients, however, have persistent, severe hypoxemia and remain ventilator-dependent. Pulmonary proliferative changes and fibrosis may progressively replace the pathological findings of diffuse alveolar damage as early as ten days after the onset of the respiratory failure. The fibroproliferative phase of ARDS is characterized radiographically by progression from airspace opacification to a more coarsely reticular pattern of lung infiltration. These changes within the lung parenchyma are often accompanied by persistent hypoxemia, low lung compliance, high dead space, and sometimes by progressive pulmonary hypertension. The course may become dominated by persistent ventilator dependence and various complications.

The lungs of patients who survive the fibroproliferative phase enter into an extended subsequent phase of resolution and repair. Hypoxemia and pulmonary infiltrates gradually improve over weeks to months. Cardiopulmonary function often returns to near baseline levels by 6 months or longer after the initial lung injury. However, many survivors of severe ARDS are left with persistent cognitive impairment, emotional disturbances, and residual muscle weakness resulting in substantially reduced quality of life [99,100].

Complications

Patients with ARDS are at high risk for complications. Some complications are related to mechanical ventilation (e.g. pulmonary barotrauma, nosocomial pneumonia), while others are related to critical illness and being in the intensive care unit (e.g. delirium, deep venous thrombosis, gastrointestinal bleeding due to stress ulceration, and catheter-related infections).

Barotrauma

Patients with ARDS are predisposed to pulmonary barotrauma due to the physical stress of positive pressure mechanical ventilation on acutely damaged alveolar membranes [101,102].

It was previously common for patients with ARDS to develop single or multiple, sequential, loculated pneumothoraces. Clinical experience suggests that such complications are less common now that low tidal volume ventilation has become widespread. This is supported by the observations that (a) low tidal volume ventilation reduces the plateau airway pressure [102] and (b) a lower plateau airway pressure is associated with a lower incidence of pulmonary barotrauma. The latter was illustrated by a systematic review of 14 clinical studies (2270 patients with ARDS) that found a strong correlation between pulmonary barotrauma and a plateau airway pressure >35 cm H2O [103].

Radiographically apparent barotrauma sometimes occurs despite an appropriate mechanical ventilation strategy and can contribute to death in patients with other risk factors for a poor outcome [104]. The pathogenesis, risk factors, prevention, presentation, diagnosis, management, and prognosis of pulmonary barotrauma are discussed in detail separately.

Delirium

ARDS and other forms of acute respiratory failure are commonly complicated by delirium [105]. Deep sedation and pharmacologically-induced neuromuscular blockade are often used to treat agitated delirium. While these interventions may contribute to adverse outcomes such as prolongation of mechanical ventilation, persistent muscle weakness [106,107], and long-term impairments in cognition and short-term memory among survivors [108], they may also optimize mechanical ventilation (i.e. mitigate derecruitment associated with patient-ventilator dyssynchrony) and prevent dislodgment of the endotracheal tube and vascular catheters. One trial found that neuromuscular blockade was associated with improved survival in patients with severe ARDS [109].

The use of sedatives and neuromuscular blocking agents in critically ill patients is reviewed separately.

Nosocomial infection

Nosocomial pneumonia is an important cause of morbidity and mortality in patients who have ARDS [110-113].

The incidence of nosocomial pneumonia among patients with ARDS is uncertain because the similar symptoms, signs, and radiographic findings make it difficult to distinguish pneumonia from the underlying ARDS [110,114]. The difficulty identifying pneumonia in patients with ARDS was illustrated by an autopsy study that found pneumonia in 58 percent of patients with ARDS, although pneumonia was suspected antemortem in only 20 percent [115]. Twenty percent of patients thought to have pneumonia did not have histologic evidence of pneumonia.

Despite the uncertainty about the incidence of nosocomial pneumonia among patients with ARDS, there is evidence that nosocomial pneumonia is more common among patients who are mechanically ventilated for ARDS than among patients who are mechanically ventilated for other reasons. This was demonstrated by an observational study of 243 consecutive patients who required mechanical ventilation, which found that patients with ARDS were significantly more likely to develop nosocomial pneumonia than patients without ARDS (55 versus 28 percent) [116]. A possible explanation for these findings is that patients with ARDS required a longer duration of mechanical ventilation.

Other complications

Other complications that frequently occur during the hospital course of patients with ARDS include the following:

  • Deep venous thrombosis
  • Gastrointestinal bleeding due to stress ulceration
  • Poor nutrition
  • Catheter-related infections

DIAGNOSTIC EVALUATION

The diagnostic evaluation is aimed at identifying specific causes of ARDS that are amenable to treatment and excluding other conditions that also present with acute hypoxemia, bilateral alveolar infiltrates, and respiratory distress. Because the current international consensus definition of ARDS specifies no criteria relating to the underlying etiology of acute bilateral inflammatory lung injury, some uncertainty remains with respect to which conditions should or should not be included under the ARDS diagnostic umbrella. Generally included are disorders that are known to cause diffuse alveolar damage and have the potential to resolve over time. Thus, viral or diffuse bacterial pneumonia and acute inhalational injuries are included, whereas eosinophilic pneumonia and diffuse alveolar hemorrhage associated with collagen vascular diseases are not. Cardiogenic pulmonary edema is the primary alternative that needs to be excluded because it is common and can be clinically indistinguishable from ARDS.

Excluding cardiogenic pulmonary edema — An absence of cardiac exam abnormalities (e.g. an S3 or S4 gallop, new or changed murmur), elevated right-sided filling pressures (e.g. elevated jugular venous pressure), and certain radiographic abnormalities (e.g. pulmonary venous congestion, Kerley B lines, cardiomegaly, and pleural effusions), helps distinguish ARDS from cardiogenic pulmonary edema. Several additional diagnostic tests may also be helpful, including measurement of plasma brain natriuretic peptide levels, echocardiography, and right heart catheterization:

  • Brain natriuretic peptide (BNP) – A plasma BNP level below 100 pg/mL favors ARDS, but higher levels neither confirm heart failure nor exclude ARDS [117,118]. This derives from an observational study of patients with ARDS (n = 33) or cardiogenic pulmonary edema (n = 21) [117]. The study found that a plasma BNP level less than 100 pg/mL identified ARDS with a sensitivity, specificity, positive predictive value, and negative predictive value of 27, 95, 90, and 44 percent, respectively.
  • Echocardiography – Many clinicians use transthoracic echocardiography as the first-line diagnostic test if cardiogenic pulmonary edema cannot be excluded by clinical evaluation and measurement of the BNP level. While severe aortic or mitral valve dysfunction, severe diastolic dysfunction, or a severely reduced left ventricular ejection fraction favors cardiogenic pulmonary edema, the latter is insufficient to confirm primary cardiogenic pulmonary edema because some precipitants of ARDS (e.g. septic shock) can cause an acute, severe cardiomyopathy that develops concomitantly with ARDS [119,120]. In addition, cardiogenic pulmonary edema cannot be excluded on the basis of an echocardiogram, since diastolic dysfunction and volume overload may exist even if the left heart function appears normal.
  • Right heart catheterization – There is ample evidence that there is generally no value to routine right heart catheterization for either the diagnosis or management of ARDS [121,122]. However, pulmonary artery catheterization may be considered if primary cardiogenic pulmonary edema cannot be excluded on the basis of the clinical evaluation, plasma BNP measurement, and echocardiogram.

Excluding other causes of hypoxemic respiratory failure — potentially treatable causes of ARDS and alternative forms of acute hypoxemic respiratory failure with bilateral infiltrates should be considered once cardiogenic pulmonary edema has been excluded. If such conditions cannot be identified on the basis of the clinical context and accompanying symptoms and signs, additional diagnostic testing should be performed:

  • Noninvasive respiratory sampling – The lower respiratory tract can be sampled via tracheobronchial aspiration or mini-bronchoalveolar lavage (mini-BAL). Tracheobronchial aspiration is performed by advancing a catheter through the endotracheal tube until resistance is met and then applying suction, while mini-BAL is performed by advancing a catheter through the endotracheal tube until resistance is met, infusing sterile saline through the catheter, and then aspirating. Regardless of the technique, the specimen that is obtained may be evaluated via microscopic analysis (e.g. Gram stain, cytology) and microbiologic culture; these studies may identify pneumonia or rapidly progressive cancer as the correct diagnosis.
  • Flexible bronchoscopy – Flexible bronchoscopy can obtain lower respiratory samples for microscopic analysis and microbiologic culture if the noninvasive techniques are unsuccessful. It can also identify abnormalities that may not be detected with noninvasive sampling. Therefore, flexible bronchoscopy is a reasonable next step whenever noninvasive sampling is nondiagnostic.
    Consider the following examples of findings that suggest a specific etiology for acute hypoxemic respiratory failure. Frothy bloody secretions throughout the airways, increasing red blood cells in serial bronchoalveolar lavage (BAL) specimens, and hemosiderin-laden macrophages in the BAL fluid suggest diffuse alveolar hemorrhage. A large number of eosinophils in the BAL fluid suggest idiopathic acute eosinophilic pneumonia. And, recovery of lipid-laden macrophages or recognizable food particles suggests aspiration pneumonitis.
  • Lung biopsy – Surgical lung biopsy may be considered when alternative causes of acute hypoxemic respiratory failure cannot be excluded on the basis of the clinical context, symptoms, signs, and bronchoscopy [123,124]. The safety of lung biopsy in selected patients with hypoxemic respiratory failure was demonstrated by a retrospective study of 57 patients with ARDS who underwent open lung biopsy [123]. The patients had a mean ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) of 145 mmHg and the rate of major complications was 7 percent, with no deaths attributed to the biopsy. Although the complication rate was 39 percent, most were tolerable (e.g. persistent air leaks). The results of the biopsy resulted in the addition of specific therapy in 60 percent of patients and the withdrawal of unnecessary therapy in 37 percent.
    Generally speaking, we believe that lung biopsy should be reserved for carefully selected patients whose acute hypoxemic respiratory failure remains of uncertain etiology after nondiagnostic flexible bronchoscopy if one or more of the diagnostic possibilities under consideration might warrant targeted therapy or would substantially change the prognosis. Examples include cryptogenic organizing pneumonia, an acute fungal lung infection, or an acute exacerbation of a chronic interstitial lung disease, vasculitis, or disseminated cancer.

DIAGNOSTIC CRITERIA

ARDS can be diagnosed once cardiogenic pulmonary edema and alternative causes of acute hypoxemic respiratory failure and bilateral infiltrates have been excluded. The Berlin Definition of ARDS requires that all of the following criteria be present to diagnose ARDS [125,126]:

  • Respiratory symptoms must have begun within one week of a known clinical insult, or the patient must have new or worsening symptoms during the past week.
  • Bilateral opacities consistent with pulmonary edema must be present on a chest radiograph or computed tomographic (CT) scan. These opacities must not be fully explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules.
  • The patient’s respiratory failure must not be fully explained by cardiac failure or fluid overload. An objective assessment (e.g. echocardiography) to exclude hydrostatic pulmonary edema is required if no risk factors for ARDS are present.
  • A moderate to severe impairment of oxygenation must be present, as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2). The severity of the hypoxemia defines the severity of the ARDS:
  • Mild ARDS – The PaO2/FiO2 is >200 mmHg, but ≤300 mmHg, on ventilator settings that include positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥5 cm H2O.
  • Moderate ARDS – The PaO2/FiO2 is >100 mmHg, but ≤200 mmHg, on ventilator settings that include PEEP ≥5 cm H2O.
  • Severe ARDS – The PaO2/FiO2 is ≤100 mmHg on ventilators setting that include PEEP ≥5 cm H2O.

To determine the PaO2/FiO2 ratio, the PaO2 is measured in mmHg and the FiO2 is expressed as a decimal between 0.21 and 1. As an example, if a patient has a PaO2 of 60 mmHg while receiving 80 percent oxygen, then the PaO2/FiO2 is 60 mmHg/0.8 = 75 mmHg. Determining the PaO2/FiO2 requires arterial blood gas (ABG) analysis, which can be difficult to obtain from some patients. For such patients, the ratio of oxyhemoglobin saturation measured by pulse oximetry (SpO2) to FiO2 is a reasonable substitute, according to a retrospective study of ABG measurements performed in adults receiving mechanical ventilation [127]. The study found that a SpO2/FiO2 of 315 predicted a PaO2/FiO2 of 300 (the threshold for ARDS) with a sensitivity of 91 percent and a specificity of 56 percent.

The Berlin Definition of ARDS (published in 2012) replaces the American-European Consensus Conference’s definition of ARDS (published in 1994) [2,128]. The major changes to the Berlin Definition are that the term “acute lung injury” has been eliminated, the pulmonary capillary wedge pressure (ie, pulmonary artery occlusion pressure) criterion has been removed, and minimal ventilator settings have been added.

DIFFERENTIAL DIAGNOSIS

A variety of alternative conditions may present as acute hypoxemic respiratory failure with bilateral alveolar infiltrates and, therefore, should be considered whenever ARDS is suspected [129].

  • Cardiogenic pulmonary edema is usually due to left ventricular systolic or diastolic dysfunction, but may also be due to fluid overload, severe hypertension, renal artery stenosis, or severe renal disease. Its presentation is nearly identical to ARDS, except there may be evidence of cardiac dysfunction (e.g. an S3 or S4 gallop, new or changed murmur), elevated right-sided filling pressures (e.g. elevated jugular venous pressure), or related radiographic abnormalities (e.g. pulmonary venous congestion, Kerley B lines, cardiomegaly, and pleural effusions). Distinguishing cardiogenic pulmonary edema from ARDS can be aided by measurement of a brain natriuretic peptide (BNP) level, echocardiography, and, less often, right heart catheterization.
  • An acute exacerbation of idiopathic pulmonary fibrosis or other chronic interstitial lung diseases can closely resemble ARDS in both clinical presentation and chest radiographic abnormalities. Like ARDS, the pathological findings are dominated by diffuse alveolar damage, but the prognosis is substantially worse. This diagnostic possibility is easily overlooked in patients whose underlying interstitial lung disease is unknown or mild or moderate in severity. The diagnosis is suggested by careful review of previous chest radiographic images, by discovery of subpleural reticulocytic changes intermixed with alveolar opacities on a chest CT scan obtained shortly after onset of ARDS, or by surgical lung biopsy.
  • Diffuse alveolar hemorrhage may be associated with a large, otherwise unexplained drop in the hemoglobin concentration and hematocrit. While hemoptysis may be minimal or absent, bronchoscopy often reveals frothy bloody secretions throughout the airways and invariably detects an increasing amount of red blood cells in serial bronchoalveolar lavage specimens. The recovery of hemosiderin-laden macrophages from bronchoalveolar lavage fluid is strongly suggestive of diffuse alveolar hemorrhage.
  • Idiopathic acute eosinophilic pneumonia (IAEP) occurs in previously healthy individuals and is characterized by cough, fever, dyspnea, and sometimes chest pain. Bronchoalveolar lavage specimens always contain a large number of eosinophils, typically 35 to 55 percent of all recovered cells [130,131]. Peripheral eosinophil may or may not be present [132].
  • Cryptogenic organizing pneumonia (COP) often mimics community-acquired pneumonia with an onset that is heralded by a flu-like illness with fever, malaise, fatigue, and cough. The most common features at presentation are a persistent nonproductive cough, dyspnea with exertion, and weight loss. Bronchoalveolar lavage usually contains a smaller proportion of macrophages and higher proportions of lymphocytes, neutrophils, and eosinophils than healthy patients. This “mixed pattern” of increased cellularity is thought to be characteristic of COP. The diagnosis is made by ruling out infectious causes of pneumonia and documenting typical pathologic changes in tissue obtained by open lung biopsy.
  • Acute interstitial pneumonia (Hamman-Rich syndrome) is a rare and fulminant form of diffuse lung injury that has a presentation similar to ARDS. Many people consider acute interstitial pneumonia a subset of idiopathic ARDS since its clinical manifestations are similar and both demonstrate diffuse alveolar damage on histopathology. The distinguishing characteristic is that ARDS is often associated with a known risk factor, whereas acute interstitial pneumonia is not.
  • Cancer can disseminate through the lungs so rapidly that the ensuing respiratory failure may be mistaken for ARDS. This is most often due to lymphoma or acute leukemia, but lymphangitic spread of solid tumors occasionally behaves this way. Cytological preparation of bronchoscopic specimens (e.g. brushings, lavage) may reveal malignant cells.

Acute respiratory distress syndrome: Prognosis and outcomes

MORTALITY

ARDS is associated with appreciable mortality, with estimates ranging from 26 to 58 percent [133-138]. The underlying cause of the ARDS is the most common cause of death among patients who die early [136,137,139,140]. In contrast, nosocomial pneumonia and sepsis are the most common causes of death among patients who die later in their clinical course [139]. Patients uncommonly die from respiratory failure [137].

Numerous studies suggest that survival has improved over time [140-142]. As an example, an observational study of 2451 patients who had enrolled in ARDSNet randomized trials found a fall in mortality from 35 to 26 percent between 1996 and 2005 [141]. Although encouraging, several issues should be considered with respect to trends in ARDS-related mortality:

  • It is not known if mortality has decreased among patients who received their care outside of a specialized center or a clinical trial.
  • The improved mortality may be attributable to patients who have ARDS related to risk factors other than sepsis, such as trauma [140].
  • To the extent that mortality has decreased, the reasons are uncertain. Likely causes include better supportive care and improved ventilatory strategies, such as low tidal volume ventilation [106,141,143].

Predictors

Many studies have sought to identify factors during the acute illness that predict mortality. Such factors can be categorized as patient-, disease-, or treatment-related. No single factor has proven to be superior to the others.

Patient-related

Older patients appear to be at an increased risk for death [134,69]. This was illustrated by a multicenter cohort study that followed 1113 patients with ARDS for 15 months [134]. The mortality rate increased progressively with age, ranging from 24 percent among patients 15 to 19 years of age to 60 percent among patients 85 years of age or older. The overall mortality rate was 41 percent.

Disease-related

Disease-related predictors of mortality include severe hypoxemia, failure of oxygenation to improve, pulmonary vascular dysfunction, increased dead space, infection, a high severity of illness score, a non-traumatic cause of the ARDS, and certain biomarkers and gene polymorphisms.

  • Oxygenation – The severity of hypoxemia determines whether the patient has mild ARDS (PaO2/FiO2 >200 but ≤300 mmHg), moderate ARDS (PaO2/FiO2 >100 but ≤200 mmHg), or severe ARDS (PaO2/FiO2 ≤100 mmHg). Mortality appears to increase as ARDS becomes more severe, according to an observational study of 3670 patients with ARDS that found that patients with mild, moderate, and severe ARDS had mortality rates of 27, 32, and 45 percent, respectively [144]. Similarly, there is general agreement that improvement of oxygenation during the early ICU course correlates with survival [145].
  • Pulmonary vascular dysfunction – Pulmonary vascular dysfunction is indicated by an elevated transpulmonary gradient (ie, ≥12 mmHg) or pulmonary vascular resistance index (ie, >285 dyne s/cm). The transpulmonary gradient is the difference between the mean pulmonary artery pressure and the pulmonary artery occlusion pressure, while the pulmonary vascular resistance index is the transpulmonary gradient divided by the cardiac index. Pulmonary vascular dysfunction appears to be an independent risk factor for 60-day mortality and fewer ventilator-free, ICU-free, and hypotension- or vasopressor-free days [146].
  • Dead space – Dead space ventilation early in the course of ARDS appears to correlate with mortality. This was illustrated by a series of 179 patients with early ARDS who had their ratio of dead space to tidal volume (ie, the dead space fraction or Vd/Vt) determined by measuring exhaled carbon dioxide (CO2) levels [147]. The dead space fraction was markedly elevated (mean 0.58, normal <0.30) and there was a linear correlation between the degree of dead space ventilation and mortality. For every 0.05 increase in dead space fraction, the odds of death increased by 45 percent.
  • Infection – Infection and/or multiorgan dysfunction are better predictors of mortality than respiratory parameters [140,148-153]. This is probably because they predict death from a nonrespiratory cause, which is more common than death due to respiratory failure.
  • Severity of illness score – Severity of illness scores appear to correlate with mortality. As an example, patients with a higher APACHE III score have an increased likelihood of death (odds ratio 1.78 per 25-point increase, 95% CI 1.16-2.73) [69].
  • Underlying cause of the ARDS – Patients with trauma-related ARDS appears to have a lower likelihood of death at 90 days than patients with ARDS that is unrelated to trauma [67].
  • Laboratory – Routine laboratory parameters are not helpful for predicting the outcome of ARDS. However, a large body of emerging evidence suggests that many biomarkers and gene polymorphisms are associated with both the susceptibility to ARDS and the outcome from ARDS [154]. The practical utility of these observations is uncertain, but the research may lead to new preventative and therapeutic strategies in the future.

Treatment-related

Treatment-related predictors of mortality include a positive fluid balance, glucocorticoid therapy prior to the onset of ARDS, packed red blood cell transfusions, and being in an ICU that does not mandate care by an Intensivist.

  • Fluid balance – A positive fluid balance may be associated with higher mortality [155,156]. This was demonstrated by the ARDSNet low tidal volume trial, which found that a negative fluid balance at day 4 was associated with decreased mortality compared to a positive fluid balance, after adjustment for factors such as age, severity of illness, and ventilator strategy (adjusted odds ratio 0.50, 95% CI 0.28-0.89) [156].
  • Treatment with glucocorticoids – Patients who received glucocorticoids prior to the onset of ARDS may have an increased likelihood of death (odds ratio 4.65, 95% CI 1.47-14.7) [69].
  • Packed red blood cell transfusion – Patients who receive packed red blood cell transfusions may have an increased likelihood of death (odds ratio 1.10 per unit transfused, 95% CI 1.04-1.17) [69,157].
  • Organization of the ICU – Patients cared for in an ICU that mandates transfer to an Intensivist or co-management by an Intensivist may have a decreased likelihood of death (odds ratio 0.68, 95% CI 0.53-0.89) [158].

MORBIDITY AMONG SURVIVORS

Survivors of ARDS frequently have persistent, abnormal exercise endurance [159-165]. The persistent nature of this abnormality was demonstrated by a prospective cohort study that followed 109 survivors of ARDS for five years [100]. The six minute walking distance at one, three, and five years was 66, 67, and 76 percent of predicted, respectively. Whether this abnormal exercise endurance is due, in part, to decreased lung function is uncertain due to conflicting data. Numerous studies have suggested that there is persistent impairment of lung function following the acute illness [159-164], while others have found little or no impairment [100,166].

A constellation of other physical and psychological problems also occur after the acute illness [161,164-169], many as long as five years after ICU discharge [100]. Examples include new physical disabilities, impaired neurocognitive function, depression, anxiety, pervasive memories of critical care, and changes to relationships, particularly with caregivers [100,170-172]. Such problems appear to be common, with one prospective cohort study estimating that the incidences of depressive symptoms and impaired physical function were 40 and 66 percent, respectively, during the two years following acute lung injury [171].

Despite these abnormalities, most survivors are able to return to work. In the prospective cohort study described above, 77 percent of those who were working at the time of their acute illness returned to work, while 17 percent did unpaid work within the home and six percent became full-time students [100]. Most of those who returned to work did so within two years after ICU discharge, although many required a gradual transition back to work.

Several studies have sought factors during the acute illness that predict long-term sequelae [162,166,173,174]:

  • Persistent symptoms one year after recovery correlate with the duration of mechanical ventilation and the lowest static thoracic compliance during the acute illness [173].
  • Abnormal lung function one year after recovery correlates with the following factors measured during the acute illness: lowest static thoracic compliance, mean pulmonary artery pressure, positive end-expiratory pressure (PEEP), initial intrapulmonary shunt fraction, and requirement of an FiO2 >0.6 for more than 24 hours [173,174].
  • A better functional outcome at one year correlates with the absence of steroid treatment, absence of illness acquired during the ICU stay, and rapid resolution of multiple organ failure and lung injury [166].
  • There is no known correlation between ventilatory strategies and either long-term pulmonary function or health-related quality of life [161,175].

Supportive care and oxygenation in acute respiratory distress syndrome

SUPPORTIVE CARE

A minority of patients with ARDS die from respiratory failure alone [176-179]. More commonly, such patients succumb to their primary illness or to secondary complications such as sepsis or multiorgan system failure.

Patients with ARDS require meticulous supportive care, including intelligent use of sedatives and neuromuscular blockade, hemodynamic management, nutritional support, control of blood glucose levels, expeditious evaluation and treatment of nosocomial pneumonia, and prophylaxis against deep venous thrombosis (DVT) and gastrointestinal (GI) bleeding.

Sedation

The use of sedative-analgesic medications in critically ill patients, including patients with ARDS, is discussed in detail separately.

Sedation and analgesia are useful in patients with ARDS because they improve tolerance of mechanical ventilation and decrease oxygen consumption [180,181]. This was illustrated by a study of seven critically ill patients, which found that the use of morphine reduced resting and total energy expenditure by 6 and 8.6 percent, respectively [181].

Since many patients with ARDS require sedation for several days or longer, long-acting relatively inexpensive agents such as Lorazepam are a logical choice [182]. Because benzodiazepines provide no analgesia, opioids (such as fentanyl or morphine) may be needed to treat pain. Opioids also provide synergy and may decrease the amount of benzodiazepine required [183]. Intermittent injections of sedative-analgesic agents are preferred, with continuous infusions reserved for patients who require repeated doses to achieve adequate sedation [184]. Occasionally, agents such as haloperidol and propofol may be useful alternatives, although the latter can be expensive, especially when used for prolonged periods [185, 186].

Several articles highlight significant morbidity associated with excessive sedation. Strategies such as routinely waking patients each day [187], using intermittent instead of continuous infusions of sedatives [188], and following a sedation and analgesia protocol [184] may lead to important benefits such as decreased time on the ventilator and fewer nosocomial infections. The avoidance of excessive sedation is discussed in detail elsewhere.

Using sedation scales such as the Richmond Agitation-Sedation Scale (RASS) may help clinicians meet sedation goals more effectively, decreasing the likelihood of over or under-sedation [184, 189]. Most patients should be manageable with light sedation (e.g. RASS of 0 or negative 1) although some patients with more severe lung injury or poor tolerance of mechanical ventilation may need to be sedated more deeply. Two studies found no evidence that increased sedation is required when patients are managed with low tidal volume as opposed to more traditional higher tidal volume ventilation [190, 191].

There is evidence that using no pharmacological sedation may be superior to using a continuous sedative infusion with daily interruption. In a single center study that enrolled patients requiring mechanical ventilation for more than 24 hours (including patients with ARDS), a protocol of no sedation was compared to the use of a continuous sedative infusion with daily interruption [192]. Patients managed without sedation received intensive non-pharmacological support, such as verbal comforting and reassurance. The no sedation group spent more time off the ventilator and less time in the ICU than those managed with continuous sedative infusions that were interrupted daily. Similar studies in patients with ARDS need to be performed to determine whether a strategy of no sedation is a viable approach in such patients.

Paralysis

Although it is widely recognized that neuromuscular blockade can have desirable effects (improves oxygenation [193]) and undesirable effects (prolonged neuromuscular weakness [130]) in patients with ARDS, the impact of these competing effects on patient-important outcomes has remained unclear. This uncertainty was addressed by a multicenter trial that randomly assigned 340 patients with ARDS to receive cisatracurium besylate or placebo by continuous infusion for 48 hours [196]. At the time of enrollment, all of the patients had been mechanically ventilated using low tidal volume ventilation and had a PaO2/FiO2 ratio of <150 mmHg on a PEEP of ≥5 cm H2O for less than 48 hours. Both groups were deeply sedated to a Ramsay sedation score of 6 (no response to glabellar tap). Patients treated with cisatracurium besylate had non-statistically significant lower crude 90-day, 28-day, hospital, and ICU mortality rates compared to the placebo group. Following a pre-specified statistical plan, the authors adjusted for baseline differences in the PaO2/FiO2, SAPS II severity score, and plateau airway pressure, and found a statistically significant decrease in 90-day mortality in patients treated with cisatracurium besylate (HR 0.68, 95% CI 0.48-0.98). The beneficial effects on 90-day mortality were limited to patients who presented with a PaO2/FiO2 ratio of less than 120 mm Hg. Patients treated with cisatracurium besylate also had significantly more ventilator-free days during the first 28 and 90 days (defined as the number of days since successful weaning from mechanical ventilation) and were significantly less likely to experience barotrauma. There was no difference in the frequency of ICU-acquired neuromuscular weakness.

We believe that these findings need to be replicated before neuromuscular blockade becomes part of the routine management of patients with early, severe ARDS. Until then, the body of evidence suggests that the administration of short-term (up to 48 hours) neuromuscular blockade to patients with ARDS who have severe gas exchange abnormalities (e.g. PaO2/FiO2 ≤120 mmHg) is probably safe and potentially beneficial. The neuromuscular blocking agents are discussed in detail separately.

Hemodynamic monitoring

Hemodynamic management guided by a central venous catheter (CVC) has been compared to that guided by a pulmonary artery catheter (PAC) in patients with ARDS [121]. In the trial, 1000 patients with ARDS were randomly assigned to receive a CVC or a PAC. There was no difference in mortality, lung function, ventilator-free days, organ failure free days, or ICU-free days at day 28. Rates of hypotension, dialysis, and vasopressor use were also the same in both groups. But, the PAC group had an approximately two-fold increase of catheter-related complications, predominantly arrhythmias. This suggests that the PAC should not be used routinely in patients with ARDS.

Nutritional support

Patients with ARDS are intensely catabolic and benefit from nutritional support [197]. If the gastrointestinal tract is available for nutritional intake, enteral feedings are preferred. Possible advantages of the enteral route include fewer intravascular infections, less GI bleeding because of gastric buffering, and preservation of the intestinal mucosal barrier, which in turn may decrease bacterial translocation across the gut. Overfeeding offers no nutritional advantage and should be avoided to prevent excessive carbon dioxide production. When patients are fed, it is essential that they be kept semirecumbent with their heads in the upright position to decrease the risk of ventilator-associated pneumonia [198].

Glucose control

The approach to glucose control in patients with ARDS is extrapolated from trials that enrolled patients with critical illness, including ARDS. This is discussed in detail elsewhere.

Nosocomial pneumonia

Nosocomial (ie, ventilator-associated) pneumonia frequently complicates the course of ARDS. As an example, one prospective study of 30 patients with severe ARDS found that nosocomial pneumonia developed in 60 percent [199]. The first episode occurred at an average of 10 days after the onset of ARDS.

Nosocomial pneumonia increases morbidity in ARDS, although the impact on mortality is less clear [114]. Given the baseline radiographic abnormalities and frequent colonization by potential pathogens, it is difficult to diagnose pneumonia in patients with ARDS on the basis of clinical factors alone [114,200].

The misdiagnosis of pneumonia in patients with ARDS may have unfortunate consequences. Inappropriate treatment of patients without pneumonia promotes the emergence of organisms with antibiotic resistance, while a missed diagnosis may be lethal. The diagnosis of ventilator-associated pneumonia is discussed in detail elsewhere.

Microbiology

Delayed, inappropriate, or inadequate antibiotic use is associated with poor outcome; therefore, it is essential to choose an initial antibiotic regimen sufficiently broad to cover likely infecting organisms [201]. Antibiotic choices should consider local sensitivity profiles, which may vary significantly from hospital to hospital.

Prevention

Nosocomial pneumonia is difficult to prevent since patients with ARDS are frequently malnourished and immunosuppressed. In addition, normal airway defenses are bypassed by the endotracheal tube (ETT), and pulmonary edema is an excellent growth medium for bacteria. Despite widespread pulmonary infiltration by neutrophils, these cells offer poor protection against invading organisms [202].

A variety of strategies have been proposed to decrease the likelihood of a patient developing nosocomial pneumonia [203]. Some studies have suggested that selective decontamination of the digestive tract can decrease the risk of pneumonia. Unfortunately, evidence supporting this practice, particularly in the medical ICU population, is uncertain at best; in addition, the procedure raises the cost of ICU care and promotes the emergence of resistant organisms [204]. Continuous subglottic aspiration may decrease infection by organisms occupying the digestive tract, but not by Pseudomonas [205].

Avoiding the supine position in mechanically ventilated patients, particularly those receiving enteral feedings, has been associated with a significant decrease in the rate of ventilator-associated pneumonia [198]. Other important considerations include avoiding unnecessary antibiotics, careful attention to mouth care, weaning patients in a timely manner to decrease the duration of mechanical ventilation, avoiding excessive sedation, avoiding ventilator circuit changes, and routinely draining ventilator circuit condensate [203].

Preliminary evidence initially suggested that closed tracheal suctioning systems might lower the incidence of ventilator-associated pneumonia (VAP). However, a more recent meta-analysis demonstrated that closed systems do not decrease the rate of VAP, mortality, or ICU length of stay [206].

DVT prophylaxis

The frequency of DVT and pulmonary embolism (PE) in patients with ARDS is unknown, but the risk is certainly high. These patients often have multiple risk factors for venous thrombosis, including prolonged immobility, trauma, activation of the coagulation pathway, and predisposing illnesses, such as obesity and malignancy. Prevention of venous thromboembolic disease is discussed elsewhere.

GI prophylaxis

Patients requiring prolonged mechanical ventilation are at increased risk for gastrointestinal bleeding [207]. Prophylaxis against stress ulcers is discussed in detail elsewhere.

MANAGEMENT OF HYPOXEMIA

By definition, patients with ARDS are severely hypoxemic. Options available for improving arterial oxygen saturation (SaO2) include:

  • Use of high fractions of inspired oxygen (FiO2)
  • Decrease oxygen consumption
  • Improve oxygen delivery
  • Manipulate mechanical ventilatory support

These options are most frequently applied in combination. Unfortunately, each modality is associated with an element of unquantifiable risk. As a result, the clinician must ultimately choose a strategy that provides adequate oxygenation (PaO2 ≥55 to 80 mmHg) while minimizing the inevitable risks.

Supplemental oxygen

Most patients require a high FiO2, especially early in ARDS when pulmonary edema is most severe [208]. Although high flow oxygen can be provided through a face mask, it is difficult to provide more than approximately 70 percent noninvasively because environmental air is entrained. By comparison, up to 100 percent oxygen is delivered easily when administered through an endotracheal tube.

Almost all patients therefore require intubation and mechanical ventilation. During the peri-intubation period, 95 to 100 percent oxygen should be given to ensure an adequate SaO2. Because oxygen uptake may exceed replenishment in areas with low V/Q ratios, some clinicians use slightly less than 100 percent oxygen (e.g. 95 percent) in an attempt to prevent absorptive atelectasis [209]. Once well established, absorptive atelectasis is not rapidly reversed by reduction of FiO2 to maintenance levels, emphasizing the desirability of rapid downward titration of FiO2 to the lowest fraction necessary to maintain an SaO2 >90 percent [210].

Although the risk of high FiO2 supplementation has not been studied specifically in patients with ARDS, it is probably significant. Studies in animals and normal humans reveal that high concentrations of oxygen damage the lung within hours, in part by forming toxic oxygen species [211-213]. The specific threshold for oxygen toxicity is unknown but appears to begin above 50 percent, and the risk rises as concentrations approach 100 percent [214]. As a result, the FiO2 should be decreased to the 50 to 60 percent range as soon as safely possible.

Mechanical ventilation strategies in patients with ARDS, including those that may allow a decrease in the FiO2 are discussed in detail elsewhere.

Fluid management

Although increased vascular permeability is the primary cause of pulmonary edema in early ARDS, the quantity of edema formed depends directly upon hydrostatic pressure, since oncotic forces are less capable of retaining fluid within the capillaries [215-217]. As a result, pulmonary edema is more likely to develop in ARDS than in the norms for any given pulmonary capillary hydrostatic pressure.

Thus, even in patients who are not volume overloaded, a strategy of conservative fluid management may help patients by reducing edema formation. This was best illustrated by a trial in which 1000 patients with established ARDS were randomly assigned to either a conservative or a liberal strategy of fluid management for seven days [218]. Patients assigned to the conservative group were managed with a fluid strategy that targeted a CVP <4 mmHg or a pulmonary artery occlusion pressure (PAOP) <8 mmHg. Patients managed with the liberal strategy targeted a CVP of 10 to 14 mmHg or a PAOP of 14 to 18 mmHg. The mean cumulative fluid balance was -136 mL in the conservative strategy group and +6992 mL in the liberal strategy group. The conservative strategy improved the oxygenation index and lung injury score, while increasing ventilator-free days (15 versus 12 days) and ICU-free days (13 versus 11 days). The 60 day mortality rate was unaltered by the fluid management strategy. Despite clearly identified CVP and PAOP goals, mean CVP and PAOP remained well above the target goals in the conservative management group, suggesting that a CVP <4 mmHg or a PAOP <8 mmHg is difficult to achieve safely with the strategies outlined in this population.

Given the clinical benefits demonstrated in this trial, we believe that a conservative strategy of fluid management is warranted in patients with ARDS, as long as hypotension and organ hypoperfusion can be avoided. It is reasonable to target a central venous pressure of <4 mmHg or a pulmonary artery occlusion pressure <8 mmHg; however, it should be recognized that such goals may be difficult to achieve. Preliminary data suggests that combination therapy with albumin and furosemide may improve fluid balance, oxygenation, and hemodynamics [219].

Ancillary measures

The need to avoid oxygen toxicity justifies the consideration of a variety of other techniques designed to improve SaO2, including diuresis, prone positioning, and strategies to decrease oxygen consumption.

Prone positioning

Prone positioning improves oxygenation in the majority of patients with ARDS. Individual studies have not shown a survival advantage, but a meta-analysis suggested a possible survival advantage among patients with the most severe hypoxemia [192]. The physiologic effects, efficacy, and application of prone ventilation are discussed in detail elsewhere.

Decrease oxygen consumption

In diseases with severe pulmonary shunting, increasing the saturation of mixed venous blood (SvO2) may increase the SaO2. Therapies that decrease oxygen consumption may improve SvO2 (and SaO2 subsequently) by decreasing the amount of oxygen extracted from the blood. Common causes of increased oxygen consumption include fever, anxiety and pain, and use of respiratory muscles; therefore, arterial saturation may improve after treatment with anti-pyretics, sedatives, analgesics, or paralytics [193,220].

Increase oxygen delivery — Oxygen delivery is determined by the following formula:

DO2 = 10 x CO x (1.34 x Hgb x SaO2 + 0.003 x PaO2)

  1. DO2 is oxygen delivered,
  2. CO is cardiac output, Hgb is hemoglobin concentration,
  3. SaO2 is the arterial oxygen saturation, and
  4. PaO2 is the partial pressure of oxygen in arterial blood.

As a result, in addition to low SaO2, DO2 may be decreased by a low Hgb and a low CO. In turn, a low DO2 may decrease SvO2.

In anemic patients, attempts to increase the hemoglobin concentration may be useful, but exceeding 9 g/dL is unlikely to increase benefit. One multicenter trial randomized 838 critically ill patients to a “restrictive” transfusion strategy to maintain the hemoglobin concentration between 7 and 9 g/dL, or to a “liberal” transfusion strategy to maintain it between 10 and 12 g/dL [221]. The 30-day mortality rates of the two groups did not differ significantly, and patients randomized to the restrictive strategy had a lower mortality rate during the period of hospitalization (22 versus 28 percent; p = 0.05).

More recent studies suggest that transfusion of packed red blood cells may increase a patient’s risk of developing ARDS and dying once ARDS is established [222]. For this reason, we suggest restricting transfusion of packed red blood cells in most ARDS patients, unless the hemoglobin falls below 7 g/dL or if there are other compelling reasons to justify transfusions.

Cardiac output may be augmented by raising filling pressures if they are low (if pulmonary edema is not exacerbated) or by using inotropic agents. However, raising oxygen delivery to supernormal levels is not clinically useful and may be harmful in some circumstances [2,223,224]. One prospective study, for example, randomized 100 patients with a variety of critical illnesses to either intravenous dobutamine or placebo if volume expansion alone failed to achieve a boost in oxygen delivery [224]. Patients in the control group received dobutamine only if their cardiac index was below 2.8 liters per minute per square meter. Despite achieving higher oxygen delivery and cardiac indices, active therapy resulted in a higher mortality (54 versus 34 percent for the control group).

Novel therapies for the acute respiratory distress syndrome

SURFACTANT

Surfactant therapy is not used to treat adults with ARDS because the evidence regarding its effect on patient-important outcomes is inconsistent. Examples of the conflicting data include the following:

  • Numerous randomized trials found no clinical benefit from recombinant surfactant protein C, synthetic surfactant, or freeze dried natural animal surfactant in patients with ARDS [225-229]. When these trials were pooled in a meta-analysis, there was again no improvement in mortality (odds ratio 0.97, 95% CI 0.73-1.30) despite a trend toward improved oxygenation (mean difference +13.18 mmHg, 95% CI, -2.95 – +29.32 mmHg) among patients treated exogenous surfactant [230].
  • In contrast, a trial that randomly assigned 153 infants, children, and adolescents to intratracheal calfactant (a type of exogenous surfactant) or placebo demonstrated decreased mortality (19 versus 33 percent for placebo) and more rapid improvement of oxygenation among patients who received calfactant [231]. A similar trial of intratracheal calfactant in adults is in progress [232].

It has been suggested that the inconsistent results may reflect differences in the formulation (ie, types and amounts of protein and phospholipid) of surfactant, population studied (ie, severity of illness, adults or children), method of drug delivery, dose, concurrent ventilation strategy, or inactivation of the delivered agent [233-235]. However, when differences in the formulation were evaluated by a meta-analysis, there were no differences in mortality when surfactant with surface protein was compared to surfactant without surface protein [230]. When differences in the severity of illness were investigated by a meta-analysis, it was found that recombinant surfactant protein C improved oxygenation and decreased mortality (26.3 versus 39.3 percent, adjusted odds ratio 0.30, 95% CI 0.11-0.82) in the subgroup of patients who had severe ARDS due to pneumonia or aspiration, but not in the overall ARDS population [236]. A subsequent trial designed to evaluate surfactant therapy in this subgroup was inconclusive because of a methodological flaw (the resuspension process partially inactivated the surfactant) [237]. Therefore, the reasons for the inconsistent results remain unknown.

The idea of using exogenous surfactant therapy to treat patients with ARDS is based upon several observations. First, the major purpose of endogenous surfactant is to prevent atelectasis. Second, multiple surfactant abnormalities (composition and function) have been described in patients with ARDS [238-240] and may be exacerbated by mechanical ventilation [235]. And, finally, atelectasis is a major contributor to hypoxemia and the propagation of lung injury in ARDS [96]. The aim of exogenous surfactant therapy is to mitigate or eliminate atelectasis caused by insufficient or abnormal surfactant by administering functional surfactant.

ANTIOXIDANTS

Antioxidant therapy with dietary oil supplementation has not become routine therapy for adults with ARDS due to inconsistent evidence. The basis of the hypothesis that antioxidant therapy might be beneficial in patients with ARDS are the observations that reactive oxygen species and partial depletion of antioxidant defense appear to be important in the establishment and propagation of ARDS, as well as evidence that indices of oxidative stress are higher among non-survivors than survivors of ARDS [241].

Examples of the conflicting data regarding dietary oil supplementation include the following:

  • Favoring dietary oil supplementation, a trial that randomly assigned 98 patients with ARDS to receive standard tube feeds or a combination of Eicosapentaenoic acid (EPA) and Gamma-linolenic acid (GLA) found that the patients who received EPA and GLA required fewer days of ventilatory support and fewer days in the ICU [242]. Moreover, another trial that randomly assigned 100 patients with ARDS to receive standard tube feeds or a combination of EPA and GLA found that patients who received EPA and GLA had better oxygenation and required a shorter duration of mechanical ventilation [243].
  • Arguing against dietary oil supplementation, more recent trials have found no effect from supplementation with dietary oils. One trial comparing a combination of omega-3 fatty acids, GLA, and antioxidants to placebo was terminated due to futility [244], while another trial comparing EPA plus docosahexaenoic acid to saline placebo found no difference in clinical outcomes [245].

Further research is needed to better understand whether the conflicting results are due to the study designs (ie, different controls), different combinations of dietary supplements, or different doses of dietary supplements.

In addition to dietary oil supplementation, two other antioxidant therapies have been studied. Lisophylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) is an agent that decreases circulating fatty acids, which have been shown to increase several-fold in patients with ARDS and act as proinflammatory mediators [246,247]. Despite promising animal data, a randomized trial comparing lisophylline to placebo in adults with ARDS was stopped after the enrollment of 235 patients because an interim analysis showed no difference in survival or other clinical end points [247]. N-acetylcysteine and L-2-oxothiazolidine-4-carboxylate (Procysteine) are agents that restore glutathione, an important antioxidant. While a trial confirmed that these therapies restored glutathione stores [248], they did not decrease the production of reactive oxygen species and they had little effect on physiological or patient-important outcomes [249,250].

GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR

Granulocyte-monocyte colony stimulating factor (gm-CSF) has not become routine therapy for adults with ARDS because the evidence is still inconclusive. As an example, in a trial that randomly assigned 131 patients with ARDS to receive either intravenous gm-CSF or placebo for 14 days, patients who received gm-CSF had lower mortality (17 versus 23 percent) and more organ failure-free days (15.7 versus 12.8 days) than patients who received placebo, but these differences were not statistically significant [251]. These findings indicate that larger trials with more events are necessary to confirm or exclude these effects. There was no difference in the number of ventilator-free days.

The hypothesis that granulocyte-monocyte colony stimulating factor (gm-CSF) may be beneficial to patients with ARDS is based upon the observation that increased gm-CSF in the bronchoalveolar lavage fluid of humans with ARDS is associated with better survival [252]. In addition, animal studies have found that gm-CSF limits epithelial cell injury and maintains alveolar macrophage function [253,254].

INHALED VASODILATORS

Inhaled vasodilators (e.g. nitric oxide, prostacyclin, prostaglandin E1) selectively dilate the vessels that perfuse well-ventilated lung zones, resulting in improved oxygenation due to better ventilation/perfusion (V/Q) matching and the amelioration of pulmonary hypertension [255]. Inhaled vasodilators have few systemic effects and rarely cause systemic hypotension since they act locally and have short half-lives.

Nitric oxide

Routine inhaled nitric oxide (NO) has not become routine therapy for adults with ARDS because, although it improves oxygenation, it has not been shown to reduce morbidity or mortality [256-259]. Instead, inhaled NO should be reserved for patients with intractable, life-threatening hypoxemia despite conventional management [260].

The evidence is best illustrated by two meta-analyses (each with over 1200 patients) that compared inhaled NO to either placebo or conventional management [9,258,259]. Both studies found that inhaled NO induced a modest, transient improvement in oxygenation, without any improvement in mortality, duration of mechanical ventilation, or ventilator-free days.
While the major effect of inhaled NO appears to be improved oxygenation, oxygenation does not improve in all patients who receive inhaled NO [255,261]. The factors that determine responsiveness are uncertain, but several have been suggested retrospective cohort studies. Patients without sepsis or septic shock may respond to inhaled NO more frequently than patients with septic shock [262]. In addition, high baseline pulmonary vascular resistance and responsiveness to positive end-expiratory pressure (PEEP) may predict a response in inhaled NO [263].

Although published guidelines endorse monitoring methemoglobin concentrations when inhaled nitric oxide is given, the risk of methemoglobinemia is rare when typical doses are used and appears to be limited to patients with methemoglobin reductase deficiency [264,265]. A meta-analysis found that inhaled NO increased the risk of renal impairment (relative risk 1.59, 95% CI 1.17 to 2.16), but did not increase the risk of bleeding, methemoglobin formation, or nitrogen dioxide formation [266]. The lack of proven outcome benefits and risk of renal impairment argue against the use of inhaled nitric oxide in settings other than refractory hypoxemia.

Prostacyclin

Routine inhaled prostacyclin has not become routine therapy for adults with ARDS because it has not been shown to improve patient-important outcomes, despite the consistent finding that it is associated with an improvement in oxygenation and a decrease in pulmonary arterial pressure [267-272]. These effects are comparable to those associated with inhaled NO. Inhaled prostacyclin should be reserved for patients with intractable, life-threatening hypoxemia despite conventional management.

The major advantage of inhaled prostacyclin compared with inhaled NO is that inhaled prostacyclin does not require sophisticated equipment for administration. Clinical experience with inhaled prostacyclin for ARDS suggests that adverse effects are infrequent, although published data are limited [273].

ANTI-INFLAMMATORY THERAPIES

Most patients who succumb to ARDS do not die from respiratory failure, but rather from complications of a prolonged stay in the intensive care unit (ICU) such as nosocomial infection or multiple organ dysfunction syndrome (MODS) [269]. Persistent inflammation may contribute to these complications and is associated with poor outcomes from ARDS; as an example, mortality is higher among patients who have large quantities of neutrophils and proinflammatory cytokines [152,274] and/or low levels of anti-inflammatory cytokines [16]. Based upon these observations, it has been hypothesized that anti-inflammatory medications might improve the outcome of ARDS.

Glucocorticoids

The role of glucocorticoids in the management of ARDS is a source of ongoing controversy. Systemic glucocorticoids clearly have a role in situations when ARDS has been precipitated by a steroid-responsive process (e.g. acute eosinophilic pneumonia) [275]. However, systemic glucocorticoid therapy has not become routine therapy for adults with other types of ARDS because its effect on mortality is uncertain and it tends to cause important side effects.

The uncertain effect of glucocorticoids on mortality is exemplified by four meta-analyses that compared systemic glucocorticoid therapy to placebo in patients with ARDS. One meta-analysis found that glucocorticoid therapy reduced mortality [276]. However, the other three meta-analyses reported a reduction of mortality that did not reach statistical significance, indicating that larger trials with more events are necessary to either confirm or exclude an effect on mortality [277-279]. Regarding other patient-important outcomes, the meta-analyses found that glucocorticoid therapy improved gas exchange, decreased the duration of mechanical ventilation, and decreased the length of stay in the ICU [276,277,279].

It has been suggested that the effects of systemic glucocorticoids vary according to when they are initiated:

  • Late: Several studies have evaluated the impact of systemic glucocorticoids during persistent ARDS, also known as the fibroproliferative phase of ARDS or late ARDS. The most notable was a double-blind trial by the ARDS Network that randomly assigned 180 patients with persistent ARDS (defined as ongoing disease 7 to 28 days after its onset) to receive methylprednisolone or placebo for 21 days [280]. Overall, there was no difference in 60-day mortality or 180-day mortality. However, there were important differences when the patients were divided according to when they received glucocorticoid therapy. In the subgroup of patients randomized 7 to 13 days after the onset of ARDS, methylprednisolone caused a non-statistically significant reduction in 60-day mortality (27 versus 36 percent) and 180-day mortality (27 versus 39 percent). In contrast, among patients randomized more than 14 days after the onset of ARDS, methylprednisolone increased 60-day mortality (35 versus 8 percent) and 180-day mortality (44 versus 12 percent). Methylprednisolone increased ventilator-free days, shock-free days, oxygenation, lung compliance, and blood pressure, but also increased neuromuscular weakness.
  • Early: Other clinical trials addressed the possibility that systemic glucocorticoids might be effective when given early in ARDS. In a double-blind trial, patients with early ARDS (defined as ≤72 hours) were randomly assigned in a 2:1 ratio to receive glucocorticoid therapy (n = 63) or placebo (n = 28) [281]. Patients in the glucocorticoid group were given methylprednisolone at 1 mg/kg per day for up to 28 days. Important features of this trial included vigilant surveillance for infection and avoidance of neuromuscular blockade. Glucocorticoid therapy reduced the duration of mechanical ventilation, length of ICU stay, and ICU mortality (21 versus 43 percent). The results of this trial are provocative, but not definitive, given the trial’s small size and imbalances in the treatment arms (including a larger number of patients with catecholamine-dependent shock in the placebo group).

Taken together, these data indicate that systemic glucocorticoid therapy should NOT be initiated 14 days or longer after the onset of ARDS and the impact of earlier therapy on mortality is uncertain. Larger trials are indicated to resolve the uncertainty regarding the effect of early systemic glucocorticoid therapy in ARDS.

The major adverse effects of systemic glucocorticoids are described separately.

Statins

Statins have not become routine therapy for adults with ARDS because they have not been shown to improve patient-important outcomes. The original idea that statin therapy might be beneficial to patients with ARDS was based upon studies that found that statins reduced the concentration of proinflammatory cytokines, reduced the inflammatory infiltrate in the interstitium, and improved survival in animal models. However, in a subsequent trial that randomly assigned 60 patients with ARDS to receive simvastatin or placebo for 14 days or until either the cessation of mechanical ventilation, the simvastatin group had non-statistically significant improvement in oxygenation and airway plateau pressure, but no change in mortality [282]. A randomized trial comparing simvastatin to placebo in patients at risk for ARDS was terminated due to minimal enrollment [283].

Macrolide antibiotics

Macrolide antibiotics have both antimicrobial and anti-inflammatory effects, and animal models suggest that these agents may have a beneficial effect in ARDS [284,285]. To evaluate the effects of macrolide antibiotics in humans with ARDS, an observational study was conducted using data from the Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) randomized trial [286]. In the observational study, 47 patients with ARDS who received a macrolide antibiotic within the initial 24 hours were compared with 188 patients who did not [287]. There was a trend toward less 180-day mortality among patients who received a macrolide antibiotic (23 versus 36 percent); after adjusting for potential confounders (e.g. patients who received a macrolide antibiotic were less likely to have received low tidal volume ventilation), the lower 180-day mortality became statistically significant (hazard ratio 0.46, 95% CI 0.23-0.92). This preliminary evidence warrants further evaluation with a controlled clinical trial.

BETA AGONISTS

Several studies have shown that beta agonists improve physiological outcomes in patients with ARDS [288-291]. As an example, a trial that randomly assigned 40 patients with ARDS to receive intravenous albuterol (15 mcg/kg per hour) or placebo for seven days found that intravenous albuterol was associated with less lung water (9 versus 13 mL/kg) and a lower plateau airway pressure (24 versus 30 cm H2O) [291]. Inhaled albuterol was not studied in the trial.

Such promising physiological evidence prompted several clinical trials to measure patient-important outcomes. One trial randomly assigned 282 patients with ARDS to receive aerosolized albuterol (5 mg) or placebo every four hours for up to ten days [292]. No differences in the mean number of ventilator-free days or hospital mortality were detected. Heart rates were higher in the albuterol group, but there was no difference in the frequency of dysrhythmias. Another trial randomly assigned 326 patients to receive intravenous salbutamol or placebo [293]. The trial was terminated due to increased mortality among patients receiving salbutamol.

While these studies indicate that beta agonists do not have a direct beneficial effect on ARDS per se, they are effective agents for treating bronchospasm in patients who have ARDS.

INEFFECTIVE OR HARMFUL THERAPIES

A number of potential therapies for ARDS were once regarded as promising, but have since proven to be either ineffective or harmful. They include the following:

  • N-acetylcysteine [249,250]
  • Procysteine (L-2-oxothiazolidine-4-carboxylate) [249]
  • Lisophylline [247]
  • Intravenous prostaglandin E1 [294,295]
  • Neutrophil elastase inhibitors [296]
  • Ibuprofen [297]
  • Activated protein C [298]
  • Ketoconazole [299-303]

Mechanical ventilation in acute respiratory distress syndrome

LOW TIDAL VOLUME VENTILATION

Low tidal volume ventilation (LTVV) is also referred to as lung protective ventilation. The rationale for this approach is that smaller tidal volumes are less likely to generate alveolar overdistension, one of the principal causes of ventilator-associated lung injury.

Benefit

The preponderance of evidence suggests that LTVV improves mortality, as well as other clinically important outcomes in patients with ARDS:

  • The multicenter ARMA trial randomly assigned 861 mechanically ventilated patients with ARDS to receive LTVV (initial tidal volume of 6 mL/kg) or conventional mechanical ventilation (initial tidal volume of 12 mL/kg) [304]. The LTVV group had a lower mortality rate (31 versus 40 percent) and more ventilator-free days (12 versus 10 days).
  • A meta-analysis of six randomized trials (1297 patients) found that LTVV significantly improved 28 day mortality (27.4 versus 37 percent, relative risk 0.74, 95% CI 0.61-0.88) and hospital mortality (34.5 versus 43.2 percent, relative risk 0.80, 95% CI 0.69-0.92), when compared to conventional mechanical ventilation [305]. This was supported by a more recent meta-analysis of four randomized trials (1149 patients) that also found that LTVV reduced hospital mortality (34.2 versus 41 percent, odds ratio 0.75, 95% CI 0.58-0.96), when compared to conventional mechanical ventilation [306].
  • In a prospective cohort study of 485 patients undergoing mechanical ventilation for ARDS, each patient’s ventilator settings were reviewed twice daily for adherence with lung protective ventilation, defined as both a tidal volume ≤6.5 mL/kg and a plateau airway pressure of ≤30 cm H2O [307]. The cohort’s two-year mortality was 64 percent; this was reduced by 7.8 percent among patients whose adherence with lung protective ventilation was 100 percent and 4 percent among patients whose adherence with lung protective ventilation was 50 percent.

Harm

LTVV is generally well tolerated. It was not associated with any clinically important adverse outcomes in the ARMA trial [304]. With respect to physiologic adverse outcomes, LTVV caused hypercapnic respiratory acidosis in some patients [308]. Hypercapnic respiratory acidosis was an expected and generally well tolerated consequence of LTVV.

Two major concerns were expressed after publication of the ARMA trial. First, the beneficial effects of LTVV may be the result of auto-PEEP rather than the low tidal volume. Second, LTVV may require increased sedation, increasing the risk of sedation-related adverse effects. These concerns have since been addressed:

  • Auto-PEEP – In theory, the higher respiratory rates that are used to maintain minute ventilation during LTVV may create auto-PEEP by decreasing the time available for complete expiration [309]. However, a subgroup analysis from the ARMA trial detected negligible quantities of auto-PEEP in both the LTVV and conventional mechanical ventilation groups [310].
  • Sedation – Work of breathing and patient-ventilator asynchrony may increase when tidal volumes are <7 mL/kg of predicted body weight (PBW) [311]. While asynchrony may require increased sedation soon after the initiation of LTVV, the need for increased sedation does not appear to persist. In a post-hoc analysis of data from a single center involved in the ARMA trial, there were no significant differences in the percentage of days patients received sedatives, opioids, or neuromuscular blockade when the LTVV group was compared to the conventional mechanical ventilation group [312].

Breath stacking is a manifestation of asynchrony that can occur despite deep sedation [313]. It causes episodic delivery of higher tidal volumes, which may undermine the benefits of LTVV. Frequent breath stacking (more than 3 stacked breaths/min) can be ameliorated by delivering slightly higher tidal volumes (7 to 8 mL/kg PBW), as long as the plateau airway pressure remains less than 30 cm H2O, or by administering additional sedation.

Application

LTVV can be performed using a protocol similar to that used in the ARMA trial [102]. The initial tidal volume is set to 8 mL/kg PBW and the initial respiratory rate is set to meet the patient’s minute ventilation requirements. Over the next one to three hours, the tidal volume is reduced to 7 mL/kg PBW and then 6 mL/kg PBW. The PBW is calculated using the following equations:

  • For females: PBW = 45.5 + 0.91*(height-152.4)
  • For males: PBW = 50 + 0.91*(height -152.4)

Where PBW is expressed in kg and height is expressed in cm.

The respiratory rate is increased (up to a maximum of 35 breaths per minute) as the tidal volume is decreased, so that the ventilator continues to deliver the patient’s entire minute ventilation.

Subsequent tidal volume adjustments are made on the basis of the plateau airway pressure, as measured using a 0.5 second inspiratory breath hold. The plateau airway pressure is checked at least every four hours and after each change in PEEP or tidal volume [102]. The goal plateau airway pressure is ≤30 cm H2O. When the plateau airway pressure is >30 cm H2O, the tidal volume is decreased in 1 mL/kg PBW increments to a minimum of 4 mL/kg PBW. Measurement of the plateau airway pressure is described separately.

A threshold plateau airway pressure below which safety is certain has not been determined. The goal plateau airway pressure of ≤30 cm H2O is based on the ARMA trial. However, a goal plateau airway pressure <28 cm H2O is more appealing since this decreases alveolar overdistension and makes it unlikely that thresholds of lung strain will be exceeded [314,315]. It seems reasonable to strive to keep the plateau airway pressure as low as possible, using LTVV even if the plateau airway pressure is already below 30 cm H2O [316].

A reasonable oxygenation goal during LTVV is an arterial oxygen tension (PaO2) between 55 and 80 mmHg or oxyhemoglobin saturation (SpO2) between 88 and 95 percent [102]. This is typically achieved by adjusting the fraction of inspired oxygen (FiO2) and the applied PEEP. The allowable combinations of FiO2 and PEEP that were used in the ARMA trial are included in the table.

The use of a written protocol outlining how to provide lung protective mechanical ventilation is associated with enhanced compliance with LTVV in patients with ARDS [317]. This approach should be considered in all institutions that provide care to such patients.

Permissive hypercapnia

LTVV frequently requires permissive hypercapnic ventilation (PHV), a ventilatory strategy that accepts alveolar hypoventilation in order to maintain a low alveolar pressure and minimize the complications of alveolar overdistension (e.g. ventilator-associated lung injury). Hypercapnia and respiratory acidosis are a consequence of this strategy.

The degree of hypercapnia can be minimized by using the highest respiratory rate that does not induce auto-PEEP and shortening the ventilator tubing to decrease dead space [318]. In addition, changing from a heat and moisture exchanger to a heated humidifier appears to decrease hypercapnia by decreasing dead space ventilation [319].

Animal studies suggest that PHV may attenuate ventilator-associated lung injury by effects that are independent of the LTVV from which it results [320,321]. It is uncertain if this effect exists in humans. In a post hoc analysis of the ARMA trial, respiratory acidosis was associated with reduced 28-day mortality in the control group, but not the LTVV group [308]. There are several reasonable interpretations of these data, including the possibility that respiratory acidosis is protective against ventilator-associated lung injury [322].

OPEN LUNG VENTILATION

Open lung ventilation is a strategy that combines low tidal volume ventilation (LTVV) and enough applied PEEP to maximize alveolar recruitment. The LTVV aims to mitigate alveolar overdistension, while the applied PEEP seeks to minimize cyclic atelectasis. Together, these effects are expected to decrease the risk of ventilator-associated lung injury.

Benefit

Some clinical trials indicate that open lung ventilation may improve mortality, other clinically important outcomes, and oxygenation. However, these trials had methodologic flaws of such importance that additional evidence is necessary before open lung ventilation is incorporated into routine clinical practice.

One multicenter trial randomly assigned 53 patients with ARDS to receive open lung ventilation or conventional ventilation [323]. The open lung ventilation group had a lower 28 day mortality (38 versus 71 percent) and hospital mortality (45 versus 71 percent), but only 28 day mortality was statistically significant. This trial had several important limitations: mortality in the control group was unexpectedly high, most of the survival benefit in the open lung ventilation group inexplicably occurred within the first three days after randomization, and the trial was conducted at two sites in Brazil where many of the patients had leptospirosis.

A second multicenter trial randomly assigned 103 patients with ARDS to receive open lung ventilation or conventional mechanical ventilation [324]. The open lung ventilation group had lower ICU mortality (32 versus 53 percent), lower hospital mortality (34 versus 56 percent), and more ventilator free days (11 versus 6 days). However, the trial had several important limitations, including that the control group was ventilated with high tidal volumes and had a mortality rate that was higher than most ARDS trials.

Harm

Open lung ventilation is generally well tolerated. It was not associated with any clinically important adverse outcomes in either of the trials described above [323,324]. With respect to physiologic adverse outcomes, the open lung ventilation group had greater hypercapnia in one of the trials [323]. This required a strategy of permissive hypercapnic ventilation, which was well tolerated.

Application

A universally accepted protocol for open lung ventilation has not been established. In general, LTVV is applied as described above and applied PEEP is set at least 2 cm above the lower inflection point of the pressure volume curve are used. Applied PEEP of 16 cm H2O is used if the lower inflection point is uncertain.

An alternative approach has been studied in which PEEP was set at a high level following a recruitment maneuver and then incrementally decreased until both the static lung compliance decreased and the oxyhemoglobin saturation decreased by two percent from the previous measurement [325]. The PEEP was then set 2 cm H2O above this level. There were no differences in any clinical outcome.

HIGH PEEP

The high PEEP approach is a type of open lung ventilation that does not require pressure-volume curves. This is advantageous because pressure-volume curves are difficult to construct and generally require neuromuscular blockade.

The rationale for delivering a high level of applied PEEP to patients with ARDS is that the applied PEEP opens collapsed alveoli, which decreases alveolar overdistension because the volume of each subsequent tidal breath is shared by more open alveoli [326,328]. If the alveoli remain open throughout the respiratory cycle, cyclic atelectasis is also reduced. Alveolar overdistension and cyclic atelectasis are the principal causes of ventilator-associated lung injury.

Benefit

The effects of high PEEP on patients with ARDS have been studied in randomized trials [135,329,330]. The trials found that high PEEP increased oxygenation and improved some clinical outcomes when compared to low PEEP. A mortality benefit was not detected, but the trials were underpowered to identify small differences or to evaluate subgroups.

The randomized trials were subsequently pooled in a meta-analysis (2299 patients), which found that patients who were mechanically ventilated using a high PEEP strategy had lower ICU mortality than those mechanically ventilated using a low PEEP strategy (28.5 versus 32.8 percent, adjusted RR 0.87, 95% CI 0.78-0.97) [331]. There was also a trend toward lower hospital mortality. The meta-analysis confirmed that high PEEP improved oxygenation, increased ventilator-free days, and decreased the need for rescue therapy (e.g. prone ventilation).

When the meta-analysis separated the 404 patients with a PaO2/FiO2 of 201 to 300 mmHg from the 1892 patients with a PaO2/FiO2 ≤200 mmHg, only those with a PaO2/FiO2 ≤200 mmHg who were mechanically ventilated using a high PEEP strategy had a lower ICU mortality (30.3 versus 36.6 percent, RR 0.85, 95% CI 0.76-0.95) [331]. There was no improvement and, possibly, worsening of both the ICU and hospital mortality among patients with a PaO2/FiO2 of 201 to 300 mmHg who were mechanically ventilated using a high PEEP strategy.

ARDS is a heterogeneous disease. Some patients have a lot of recruitable lung, while others have little recruitable lung as defined by CT scan [332]. It has been suggested that the benefits of high PEEP have been underestimated because its advantages in patients with a lot of recruitable lung were mitigated by its detrimental effects in patients with little recruitable lung [333]. This notion was supported by a study that found that high PEEP reduced cyclic atelectasis to a greater extent than it increased alveolar strain among patients with a lot of recruitable lung [334]. In contrast, it increased alveolar strain without reducing cyclic atelectasis among patients with little recruitable lung. Future trials comparing higher levels of PEEP to lower levels should be restricted to patients with a significant amount of recruitable lung, since this population is most likely to benefit from high PEEP.

Harm

Increased applied PEEP has the potential to cause pulmonary barotrauma or ventilator-associated lung injury by increasing the plateau airway pressure and causing alveolar overdistension. It also has the potential to decrease blood pressure by reducing cardiac output [329,335]. However, these adverse effects have not been universally reported [135].

Application

A universally accepted method for applying high PEEP has not been established, in part because the randomized trials have used different approaches. As an example, the ALVEOLI trial used a table of allowable combinations of applied PEEP and FiO2, while another trial applied the highest PEEP possible until a plateau airway pressure of 28 to 30 cm H2O was reached [329]. The high PEEP strategy was combined with LTVV in both trials.

Presently, there is insufficient evidence to recommend a single approach for selecting the optimal level of PEEP when using a strategy of high PEEP. For most centers, reasonable approaches include either adopting the allowable combinations of PEEP and FiO2 used in the high PEEP arm of the ALVEOLI trial or applying the highest PEEP possible until a plateau airway pressure of 28 to 30 cm H2O is reached. Techniques incorporating esophageal pressure measurements or static pressure-volume curves to identify the optimal PEEP may be considered in centers with the appropriate expertise, but additional research is required before these approaches are more broadly recommended.

RECRUITMENT MANEUVERS

A recruitment maneuver is the brief application of a high level of continuous positive airway pressure, such as 35 to 40 cm H2O for 40 seconds. Most studies of recruitment maneuvers have looked at physiologic outcomes, such as oxygenation [336-339]. The impact of routine recruitment maneuvers on clinical outcomes is unclear, although one meta-analysis found that recruitment maneuvers did not affect mortality, length of hospital stay, or the incidence of barotrauma, despite improving the PaO2 [340]. We believe that there is insufficient evidence to support the routine use of recruitment maneuvers in patients with ARDS. However, the possibility that some patients with ARDS may benefit from recruitment maneuvers cannot be excluded, since patients with ARDS are a heterogeneous population.

The purpose of recruitment maneuvers is to open alveoli that have collapsed [341]. There is no consensus regarding the best level of continuous positive airway pressure or the optimal frequency or duration of the maneuvers, although one study found that most of the alveolar recruitment occurred during the first ten seconds of the maneuver [342]. This was followed by a decrease in the blood pressure, which recovered within 30 seconds after the recruitment maneuver. Significant alveolar overdistension does not appear to occur during a single recruitment maneuver (but may occur with frequent recruitment maneuvers) and the recruited alveoli tend to remain open when lower airway pressures are reinstituted [341,343,344].

The arterial oxygen tension (PaO2) generally increases after a recruitment maneuver [339]. The magnitude of the increase is greatest when the recruitment maneuver is followed by high levels of PEEP (e.g. 16 cm H2O), compared to when it is followed by lower levels of PEEP (e.g. 9 cm H2O) [345]. Some investigators have used a recruitment maneuver as a starting point from which to titrate PEEP to a minimally effective level [325].

Recruitment maneuvers may be particularly beneficial after a patient has been disconnected from the ventilator (e.g. tubing changes, transport) because even a brief moment without PEEP can result in alveolar collapse [346,347]. The most common adverse effects of recruitment maneuvers are hypotension and desaturation [339]. These effects are generally self-limited and without serious consequences.

Sigh breaths are a type of recruitment maneuver characterized by the cyclic administration of a high level of continuous positive airway pressure for brief periods. As an example, a patient may receive three sigh breaths per minute at a level of 45 cm H2O [348]. While some studies suggest that sigh breaths may be most beneficial for patients undergoing prone ventilation or patients with extrapulmonary causes of ARDS, other studies do not [349-351].

OTHER CONSIDERATIONS

There are several other important considerations regarding mechanical ventilation in ARDS. These include whether a trial of noninvasive mechanical ventilation should be performed, the preferred mode of mechanical ventilation, what to do if there is refractory hypoxemia, how to optimally titrate PEEP during low tidal volume ventilation (LTVV), and whether to use neuromuscular blockade.

Invasive versus noninvasive

Most clinicians use invasive mechanical ventilation for patients with ARDS because there is little clinical experience using noninvasive positive pressure ventilation (NPPV). However, NPPV may be considered in the occasional patient with ARDS who is hemodynamically stable, able to tolerate wearing a face mask, and able to maintain a patent airway. Additional studies are necessary before more precise recommendations can be provided about the role of NPPV, since the current evidence is so limited.

A small (n = 40) trial randomly assigned patients with ARDS to receive either NPPV or high concentration supplemental oxygen [352]. Patients receiving NPPV were more likely to have improvement of PaO2/FiO2 and less likely to require intubation (4.8 versus 36.8 percent). Several limitations undermine the conclusions that can be drawn from this trial. First, the study was small and, therefore, the estimated effect size should be considered imprecise and the risk of adverse events may have been underestimated. Second, selection bias may have been introduced since many participating physicians appeared to have favored NPPV. Third, caregivers were not blinded and this could have influenced decisions to intubate. Finally, patients greater than 70 years of age, with multiple organ failure, or a PaO2/FiO2 <200 were excluded from participation and, therefore, the findings of this study cannot be applied to such patients.

Mode

Patients with ARDS can be supported using either a volume limited or a pressure limited mode of ventilation. In most patients with ARDS, a volume limited mode will produce a stable airway pressure and a pressure limited mode will deliver stable tidal volumes, assuming that breath to breath lung mechanics and patient effort are stable. Abrupt changes in the airway pressure in a patient receiving volume limited ventilation, or in tidal volumes in the patient receiving pressure limited ventilation, should prompt an immediate search for a cause of an acute change in compliance (e.g. pneumothorax or an obstructed endotracheal tube).

In order to adhere to a strategy of LTVV, it is probably easier to use a volume limited approach. However, a pressure limited mode is an acceptable alternative, as long as the resulting tidal volumes are stable and consistent with the strategy of LTVV.

Regardless of whether volume limited or pressure limited ventilation is chosen, fully supported modes of mechanical ventilation (e.g. assist control) are generally favored over partially supported modes (e.g. synchronized intermittent mandatory ventilation [SIMV]). This is particularly true early in the course of disease. Ultimately, the choice of mode depends primarily on clinician comfort and familiarity.

Alternative modes of mechanical ventilation (e.g. airway pressure release ventilation, high frequency ventilation) have also been used in patients with ARDS. While these modes may be useful in occasional patients who fail traditional approaches, the lack of outcome data precludes a recommendation for their routine use. These modes are described separately.

Refractory hypoxemia

Refractory hypoxemia can occur even if the applied PEEP and FiO2 are optimized. In this situation, increasing the I:E ratio by prolonging inspiratory time may improve oxygenation. The inspiratory time can be directly set during pressure limited ventilation. It is indirectly prolonged during volume limited ventilation by decreasing the inspiratory flow rate, changing from a square wave to a decelerating wave, or providing an end inspiratory breath hold. Increasing the I:E ratio will increase the mean airway pressure and may improve oxygenation in some patients [353-356].

Prolonging the inspiratory time can be an effective means of improving oxygenation in some patients with ARDS because the parenchymal abnormalities are heterogeneous, with different areas of the lung requiring more time to open and participate in gas exchange. It can be considered in patients who remain severely hypoxemic despite a high FiO2.

There are potential costs associated with prolonging the inspiratory time that should be considered. When the inspiratory time is increased, there is an obligatory decrease in the expiratory time. This can lead to air trapping, auto-PEEP, barotrauma, hemodynamic instability, and decreased oxygen delivery. In addition, a prolonged inspiratory time may require significant sedation or neuromuscular blockade, particularly if the inspiratory time surpasses the expiratory time (inverse ratio ventilation).

In addition to inverse ratio ventilation, high applied PEEP should be administered to patients with refractory hypoxemia before implementing other rescue interventions (e.g. high frequency ventilation). The rationale is that ARDS patients are a heterogeneous group, some of whom may have large areas of recruitable lung that will respond to applied PEEP.

Titrating PEEP

The goal of applied PEEP in patients with ARDS is to maximize alveolar recruitment and to prevent cycles of recruitment and decruitment. An optimal approach to setting applied PEEP has not been established [357]. Titration according to physiologic measures is of theoretical, but unproven, benefit. This section describes some of the approaches to titrating applied PEEP that have been studied, although there are insufficient data to support the routine use of such strategies.

Esophageal pressure

Esophageal pressure is an estimate of pleural pressure. It can be measured with an esophageal balloon catheter and then used to calculate the transpulmonary pressure:

Transpulmonary pressure = airway pressure – pleural pressure

The transpulmonary pressure can then be adjusted by titrating applied PEEP, since airway pressure is related to the applied PEEP. Titrating applied PEEP to an end-expiratory transpulmonary pressure between 0 and 10 cm H2O may reduce cyclic alveolar collapse, while maintaining an end-inspiratory transpulmonary pressure ≤25 cm H2O may reduce alveolar overdistension [358].

The value of measuring esophageal pressure was evaluated in a trial that randomly assigned 61 patients with ARDS to one of the following mechanical ventilation strategies [358]:

  • Adjustment of the FiO2 and applied PEEP to achieve specific transpulmonary pressures, as measured with an esophageal balloon during an end-expiratory occlusion maneuver
  • Adjustment of the FiO2 and applied PEEP according to a table of ventilator combinations, an approach similar to that used in the ARMA trial described above

Both strategies were designed to maintain an arterial oxygen tension (PaO2) between 55 and 120 mmHg, or oxyhemoglobin saturation between 88 and 98 percent. The group whose applied PEEP was guided by esophageal pressure measurements was managed with significantly higher total PEEP (18 versus 12 cm H2O) and had a significantly higher PaO2/FiO2 ratio (280 versus 191 mmHg), both assessed at 72 hours. The esophageal pressure group also had an almost statistically significant reduction in 28-day mortality (17 versus 39 percent, adjusted relative risk 0.46, 95% CI 0.19 to 1.00). There was no difference in the number of ICU-free days or ventilator-free days.

We believe esophageal pressure-guided mechanical ventilation should not be used routinely in most centers until larger trials are performed investigating clinically important outcomes, such as mortality [359]. Improved oxygenation alone is insufficient to warrant a change in routine clinical practice because prior studies have NOT shown an association between survival and improved oxygenation, particularly when the latter is achieved with a potentially harmful mechanical ventilation strategy [102]. It is difficult for most centers to justify the inconvenience and cost of obtaining the necessary equipment and expertise without more certain evidence of clinical benefit. However, in centers that already have the necessary equipment and expertise, esophageal pressure-guided mechanical ventilation may be helpful in the management of patients with ARDS, especially if there are concerns that airway pressures do not accurately reflect distending pressures in the lung (e.g. when there is external compression of the lung due to abdominal compartment syndrome, chest wall deformities, or large pleural effusion).

PV curves

In many patients with early ARDS, pressure-volume (PV) curves appear flat at low lung volumes (low compliance), become steeper at higher lung volumes (higher compliance), and then flatten again at even higher lung volumes. The lower inflection point is the transition from low to higher compliance, while the upper inflection point is the transition from higher to low compliance. There are two methods of titrating applied PEEP that require a PV curve:

  • The first method involves using a level of applied PEEP that is slightly above the lower inflection point [360-362]. The trials of open lung ventilation described above are examples of this method. Specifically, they used an applied PEEP that was 2 cm H2O greater than the lower inflection point that was chosen.
  • The second method involves using a level of applied PEEP that matches the pressure at which lung compliance is maximized. This is determined from the PV curve (slope equals compliance) or by stepwise titration of applied PEEP with calculation of compliance at each step [57,363]. Compliance is calculated using the equation Crs = VT/(Ppl – PEEP), where Crs is the compliance, VT is the tidal volume, and Ppl is the plateau airway pressure. Measurement of the plateau airway pressure is described separately.

Regardless of which method is chosen, inflation beyond the upper inflection point can result in alveolar overdistension and pulmonary barotrauma, as well as impaired cardiac filling and oxygen delivery [364].

There are significant limitations to using PV curves to identify the level of applied PEEP necessary for open lung ventilation [343,357,365-369]. Among the limitations, the lower inflection point cannot be identified in some patients and neuromuscular blockade or apneic-level sedation is generally required to accurately construct a PV curve [357,365]. A novel approach to plotting a pressure-volume curve that doesn’t require neuromuscular blockade has been used in several clinical trials [332,366]. Following five cycles of controlled ventilation, the inspiratory to expiratory ratio is set to 80 percent, the respiratory rate is set to five breaths per minute, and the tidal volume is set to 500 mL [371]. Inspiratory flow is then administered for 9.6 seconds, during which a PV curve is generated on the ventilator screen. From this curve, the lower inflection point can be determined. This approach appears promising, but requires validation.

Oxygenation

Applied PEEP can be titrated according to oxygenation. The lowest level of applied PEEP at which an adequate PaO2 is maintained (with the FiO2 is less than 0.6) is used for ongoing mechanical ventilation [372].

Lung ultrasound

The effects of applied PEEP on lung aeration can be directly visualized by lung ultrasound [373]. While this may prove useful in the future, additional experience is necessary before lung ultrasound is used to titrate PEEP in patients with ARDS.

Oxygen delivery

Applied PEEP can be titrated to a maximum oxygen delivery (DO2). This method involves calculating the DO2 at each level of applied PEEP, then using the applied PEEP that corresponds with the best DO2 for ongoing mechanical ventilation. The calculation of DO2 is discussed elsewhere.

Neuromuscular blockade

It has been hypothesized that neuromuscular blockade might benefit patients with ARDS by eliminating ventilator asynchrony and reducing chest wall elastance, leading to a favorable transpulmonary pressure and equitable distribution of delivered gas. The impact of early neuromuscular blockade on clinical outcomes in patients with severe ARDS is discussed in detail separately [374].

References

  1. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818.
  2. Artigas A, Bernard GR, Carlet J, et al. The American-European Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 157:1332.
  3. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353:1685.
  4. Frutos-Vivar F, Nin N, Esteban A. Epidemiology of acute lung injury and acute respiratory distress syndrome. Curr Opin Crit Care 2004; 10:1.
  5. Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome. Crit Care Med 2002; 30:2450.
  6. Esteban A, Anzueto A, Frutos F, et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 2002; 287:345.
  7. Zaccardelli DS, Pattishall EN. Clinical diagnostic criteria of the adult respiratory distress syndrome in the intensive care unit. Crit Care Med 1996; 24:247.
  8. MacCallum NS, Evans TW. Epidemiology of acute lung injury. Curr Opin Crit Care 2005; 11:43.
  9. Li G, Malinchoc M, Cartin-Ceba R, et al. Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 2011; 183:59.
  10. George RB, Chesson AL, Rennard SI. Functional anatomy of the respiratory system. In: Chest Medicine. Essentials of Pulmonary and Critical Care Medicine, 3rd ed, George RB, Light RW, Matthay MA, et al (Eds), Williams & Wilkins, Baltimore 1995. p.3.
  11. Matthay MA. Acute hypoxemic respiratory failure: Pulmonary edema and ARDS. In: Chest Medicine. Essentials of Pulmonary and Critical Care Medicine, 3rd ed, George RB, Light RW, Matthay MA, et al (Eds), Williams & Wilkins, Baltimore 1995. p.593.
  12. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med 2004; 141:460.
  13. Parsons PE, Eisner MD, Thompson BT, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005; 33:1.
  14. Martin TR. Lung cytokines and ARDS: Roger S. Mitchell Lecture. Chest 1999; 116:2S.
  15. Colletti LM, Remick DG, Burtch GD, et al. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 1990; 85:1936.
  16. Donnelly SC, Strieter RM, Reid PT, et al. The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Ann Intern Med 1996; 125:191.
  17. Miller EJ, Cohen AB, Matthay MA. Increased interleukin-8 concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis. Crit Care Med 1996; 24:1448.
  18. Chollet-Martin S, Gatecel C, Kermarrec N, et al. Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation. Am J Respir Crit Care Med 1996; 153:985.
  19. Windsor AC, Mullen PG, Fowler AA, Sugerman HJ. Role of the neutrophil in adult respiratory distress syndrome. Br J Surg 1993; 80:10.
  20. Hogg JC. Felix Fleischner Lecture. The traffic of polymorphonuclear leukocytes through pulmonary microvessels in health and disease. AJR Am J Roentgenol 1994; 163:769.
  21. Roumen RM, Hendriks T, de Man BM, Goris RJ. Serum lipofuscin as a prognostic indicator of adult respiratory distress syndrome and multiple organ failure. Br J Surg 1994; 81:1300.
  22. Gadek JE, Pacht ER. The interdependence of lung antioxidants and antiprotease defense in ARDS. Chest 1996; 110:273S.
  23. Donnelly SC, MacGregor I, Zamani A, et al. Plasma elastase levels and the development of the adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151:1428.
  24. Calandrino FS Jr, Anderson DJ, Mintun MA, Schuster DP. Pulmonary vascular permeability during the adult respiratory distress syndrome: a positron emission tomographic study. Am Rev Respir Dis 1988; 138:421.
  25. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 163:1376.
  26. Dantzker DR, Brook CJ, Dehart P, et al. Ventilation-perfusion distributions in the adult respiratory distress syndrome. Am Rev Respir Dis 1979; 120:1039.
  27. Kiiski R, Takala J, Kari A, Milic-Emili J. Effect of tidal volume on gas exchange and oxygen transport in the adult respiratory distress syndrome. Am Rev Respir Dis 1992; 146:1131.
  28. Roupie E, Dambrosio M, Servillo G, et al. Titration of tidal volume and induced hypercapnia in acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152:121.
  29. Gattinoni L, Pesenti A, Avalli L, et al. Pressure-volume curve of total respiratory system in acute respiratory failure. Computed tomographic scan study. Am Rev Respir Dis 1987; 136:730.
  30. Vieillard-Baron A, Schmitt JM, Augarde R, et al. Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis. Crit Care Med 2001; 29:1551.
  31. Villar J, Blazquez MA, Lubillo S, et al. Pulmonary hypertension in acute respiratory failure. Crit Care Med 1989; 17:523.
  32. Steltzer H, Krafft P, Fridrich P, et al. Right ventricular function and oxygen transport patterns in patients with acute respiratory distress syndrome. Anaesthesia 1994; 49:1039.
  33. Morelli A, Teboul JL, Maggiore SM, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 2006; 34:2287.
  34. Melot C, Naeije R, Mols P, et al. Pulmonary vascular tone improves pulmonary gas exchange in the adult respiratory distress syndrome. Am Rev Respir Dis 1987; 136:1232.
  35. Monchi M, Bellenfant F, Cariou A, et al. Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med 1998; 158:1076.
  36. Wright PE, Bernard GR. The role of airflow resistance in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1989; 139:1169.
  37. Wright PE, Carmichael LC, Bernard GR. Effect of bronchodilators on lung mechanics in the acute respiratory distress syndrome (ARDS). Chest 1994; 106:1517.
  38. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990; 11:593.
  39. Gattinoni L, Pelosi P, Suter PM, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med 1998; 158:3.
  40. Lim CM, Jung H, Koh Y, et al. Effect of alveolar recruitment maneuver in early acute respiratory distress syndrome according to antiderecruitment strategy, etiological category of diffuse lung injury, and body position of the patient. Crit Care Med 2003; 31:411.
  41. Tugrul S, Akinci O, Ozcan PE, et al. Effects of sustained inflation and postinflation positive end-expiratory pressure in acute respiratory distress syndrome: focusing on pulmonary and extrapulmonary forms. Crit Care Med 2003; 31:738.
  42. Rocco PR, Zin WA. Pulmonary and extrapulmonary acute respiratory distress syndrome: are they different? Curr Opin Crit Care 2005; 11:10.
  43. Pepe PE, Potkin RT, Reus DH, et al. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 1982; 144:124.
  44. Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151:293.
  45. Fowler AA, Hamman RF, Good JT, et al. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983; 98:593.
  46. Villar J, Blanco J, Añón JM, et al. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011; 37:1932.
  47. Doyle RL, Szaflarski N, Modin GW, et al. Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818.
  48. Fein AM, Lippmann M, Holtzman H, et al. The risk factors, incidence, and prognosis of ARDS following septicemia. Chest 1983; 83:40.
  49. Moss M, Bucher B, Moore FA, et al. The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 1996; 275:50.
  50. Moss M, Parsons PE, Steinberg KP, et al. Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med 2003; 31:869.
  51. Iscimen R, Cartin-Ceba R, Yilmaz M, et al. Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med 2008; 36:1518.
  52. Moss M, Guidot DM, Wong-Lambertina M, et al. The effects of chronic alcohol abuse on pulmonary glutathione homeostasis. Am J Respir Crit Care Med 2000; 161:414.
  53. Foreman MG, Hoor TT, Brown LA, Moss M. Effects of chronic hepatic dysfunction on pulmonary glutathione homeostasis. Alcohol Clin Exp Res 2002; 26:1840.
  54. Burnham EL, Moss M, Harris F, Brown LA. Elevated plasma and lung endothelial selectin levels in patients with acute respiratory distress syndrome and a history of chronic alcohol abuse. Crit Care Med 2004; 32:675.
  55. Tietjen PA, Kaner RJ, Quinn CE. Aspiration emergencies. Clin Chest Med 1994; 15:117.
  56. MENDELSON CL. The aspiration of stomach contents into the lungs during obstetric anesthesia. Am J Obstet Gynecol 1946; 52:191.
  57. Wynne JW. Aspiration pneumonitis. Correlation of experimental models with clinical disease. Clin Chest Med 1982; 3:25.
  58. Baumann WR, Jung RC, Koss M, et al. Incidence and mortality of adult respiratory distress syndrome: a prospective analysis from a large metropolitan hospital. Crit Care Med 1986; 14:1.
  59. Mannes GP, Boersma WG, Baur CH, Postmus PE. Adult respiratory distress syndrome (ARDS) due to bacteraemic pneumococcal pneumonia. Eur Respir J 1991; 4:503.
  60. Pachon J, Prados MD, Capote F, et al. Severe community-acquired pneumonia. Etiology, prognosis, and treatment. Am Rev Respir Dis 1990; 142:369.
  61. Torres A, Serra-Batlles J, Ferrer A, et al. Severe community-acquired pneumonia. Epidemiology and prognostic factors. Am Rev Respir Dis 1991; 144:312.
  62. Demling RH. Current concepts on the adult respiratory distress syndrome. Circ Shock 1990; 30:297.
  63. Sutyak JP, Wohltmann CD, Larson J. Pulmonary contusions and critical care management in thoracic trauma. Thorac Surg Clin 2007; 17:11.
  64. Schonfeld SA, Ploysongsang Y, DiLisio R, et al. Fat embolism prophylaxis with corticosteroids. A prospective study in high-risk patients. Ann Intern Med 1983; 99:438.
  65. Moore FA, Moore EE, Read RA. Postinjury multiple organ failure: role of extrathoracic injury and sepsis in adult respiratory distress syndrome. New Horiz 1993; 1:538.
  66. Treggiari MM, Hudson LD, Martin DP, et al. Effect of acute lung injury and acute respiratory distress syndrome on outcome in critically ill trauma patients. Crit Care Med 2004; 32:327.
  67. Calfee CS, Eisner MD, Ware LB, et al. Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders. Crit Care Med 2007; 35:2243.
  68. Ketai LH, Grum CM. C3a and adult respiratory distress syndrome after massive transfusion. Crit Care Med 1986; 14:1001.
  69. Gong MN, Thompson BT, Williams P, et al. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 2005; 33:1191.
  70. Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol 2007; 136:788.
  71. Khan H, Belsher J, Yilmaz M, et al. Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 2007; 131:1308.
  72. Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2004; 170:22.
  73. Parsons PE. Respiratory failure as a result of drugs, overdoses, and poisonings. Clin Chest Med 1994; 15:93.
  74. Reed CR, Glauser FL. Drug-induced noncardiogenic pulmonary edema. Chest 1991; 100:1120.
  75. Borish L, Matloff SM, Findlay SR. Radiographic contrast media-induced noncardiogenic pulmonary edema: case report and review of the literature. J Allergy Clin Immunol 1984; 74:104.
  76. Guidot DM, Hart CM. Alcohol abuse and acute lung injury: epidemiology and pathophysiology of a recently recognized association. J Investig Med 2005; 53:235.
  77. Marshall RP, Webb S, Hill MR, et al. Genetic polymorphisms associated with susceptibility and outcome in ARDS. Chest 2002; 121:68S.
  78. Gong MN, Wei Z, Xu LL, et al. Polymorphism in the surfactant protein-B gene, gender, and the risk of direct pulmonary injury and ARDS. Chest 2004; 125:203.
  79. Lin Z, Pearson C, Chinchilli V, et al. Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clin Genet 2000; 58:181.
  80. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 166:646.
  81. Villar J, Flores C, Pérez-Méndez L, et al. Angiotensin-converting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome. Intensive Care Med 2008; 34:488.
  82. Iribarren C, Jacobs DR Jr, Sidney S, et al. Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting. Chest 2000; 117:163.
  83. Calfee CS, Matthay MA, Eisner MD, et al. Active and passive cigarette smoking and acute lung injury after severe blunt trauma. Am J Respir Crit Care Med 2011; 183:1660.
  84. Messent M, Sullivan K, Keogh BF, et al. Adult respiratory distress syndrome following cardiopulmonary bypass: incidence and prediction. Anaesthesia 1992; 47:267.
  85. Asimakopoulos G, Smith PL, Ratnatunga CP, Taylor KM. Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac Surg 1999; 68:1107.
  86. Dulu A, Pastores SM, Park B, et al. Prevalence and mortality of acute lung injury and ARDS after lung resection. Chest 2006; 130:73.
  87. De Campos T, Deree J, Coimbra R. From acute pancreatitis to end-organ injury: mechanisms of acute lung injury. Surg Infect (Larchmt) 2007; 8:107.
  88. Anzueto A, Frutos-Vivar F, Esteban A, et al. Influence of body mass index on outcome of the mechanically ventilated patients. Thorax 2011; 66:66.
  89. Gong MN, Bajwa EK, Thompson BT, Christiani DC. Body mass index is associated with the development of acute respiratory distress syndrome. Thorax 2010; 65:44.
  90. Cohen DS, Matthay MA, Cogan MG, Murray JF. Pulmonary edema associated with salt water near-drowning: new insights. Am Rev Respir Dis 1992; 146:794.
  91. Modell JH. Drowning. N Engl J Med 1993; 328:253.
  92. Clark MC, Flick MR. Permeability pulmonary edema caused by venous air embolism. Am Rev Respir Dis 1984; 129:633.
  93. Gajic O, Dabbagh O, Park PK, et al. Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med 2011; 183:462.
  94. Trillo-Alvarez C, Cartin-Ceba R, Kor DJ, et al. Acute lung injury prediction score: derivation and validation in a population-based sample. Eur Respir J 2011; 37:604.
  95. Goodman LR. Congestive heart failure and adult respiratory distress syndrome. New insights using computed tomography. Radiol Clin North Am 1996; 34:33.
  96. Gattinoni L, Presenti A, Torresin A, et al. Adult respiratory distress syndrome profiles by computed tomography. J Thorac Imaging 1986; 1:25.
  97. Pelosi P, Crotti S, Brazzi L, Gattinoni L. Computed tomography in adult respiratory distress syndrome: what has it taught us? Eur Respir J 1996; 9:1055.
  98. Rubenfeld GD, Caldwell E, Granton J, et al. Interobserver variability in applying a radiographic definition for ARDS. Chest 1999; 116:1347.
  99. Rubenfeld GD, Caldwell E, Granton J, et al. Interobserver variability in applying a radiographic definition for ARDS. Chest 1999; 116:1347.
  100. Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364:1293.
  101. Gammon RB, Shin MS, Groves RH Jr, et al. Clinical risk factors for pulmonary barotrauma: a multivariate analysis. Am J Respir Crit Care Med 1995; 152:1235.
  102. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301.
  103. Boussarsar M, Thierry G, Jaber S, et al. Relationship between ventilatory settings and barotrauma in the acute respiratory distress syndrome. Intensive Care Med 2002; 28:406.
  104. Schnapp LM, Chin DP, Szaflarski N, Matthay MA. Frequency and importance of barotrauma in 100 patients with acute lung injury. Crit Care Med 1995; 23:272.
  105. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001; 29:1370.
  106. Artigas A, Bernard GR, Carlet J, et al. The American-European Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 157:1332.
  107. Bercker S, Weber-Carstens S, Deja M, et al. Critical illness polyneuropathy and myopathy in patients with acute respiratory distress syndrome. Crit Care Med 2005; 33:711.
  108. Van den Boogaard M, Schoonhoven L, Evers AW, et al. Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning. Crit Care Med 2012; 40:112.
  109. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010; 363:1107.
  110. Seidenfeld JJ, Pohl DF, Bell RC, et al. Incidence, site, and outcome of infections in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1986; 134:12.
  111. Kollef MH, Silver P, Murphy DM, Trovillion E. The effect of late-onset ventilator-associated pneumonia in determining patient mortality. Chest 1995; 108:1655.
  112. Fagon JY, Chastre J, Vuagnat A, et al. Nosocomial pneumonia and mortality among patients in intensive care units. JAMA 1996; 275:866.
  113. Fagon JY, Chastre J, Hance AJ, et al. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med 1993; 94:281.
  114. Sutherland KR, Steinberg KP, Maunder RJ, et al. Pulmonary infection during the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152:550.
  115. Andrews CP, Coalson JJ, Smith JD, Johanson WG Jr. Diagnosis of nosocomial bacterial pneumonia in acute, diffuse lung injury. Chest 1981; 80:254.
  116. Chastre J, Trouillet JL, Vuagnat A, et al. Nosocomial pneumonia in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 157:1165.
  117. Levitt JE, Vinayak AG, Gehlbach BK, et al. Diagnostic utility of B-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study. Crit Care 2008; 12:R3.
  118. Rudiger A, Gasser S, Fischler M, et al. Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure. Crit Care Med 2006; 34:2140.
  119. Bouhemad B, Nicolas-Robin A, Arbelot C, et al. Acute left ventricular dilatation and shock-induced myocardial dysfunction. Crit Care Med 2009; 37:441.
  120. Landesberg G, Gilon D, Meroz Y, et al. Diastolic dysfunction and mortality in severe sepsis and septic shock. Eur Heart J 2012; 33:895.
  121. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wheeler AP, Bernard GR, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:2213.
  122. Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003; 290:2713.
  123. Patel SR, Karmpaliotis D, Ayas NT, et al. The role of open-lung biopsy in ARDS. Chest 2004; 125:197.
  124. Papazian L, Thomas P, Bregeon F, et al. Open-lung biopsy in patients with acute respiratory distress syndrome. Anesthesiology 1998; 88:935.
  125. The ARDS Definition Task Force. Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA 2012; May 21, 2012:Epub ahead of print.
  126. Ferguson ND, Fan E, Camporota L, et al. The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 2012; 38:1573.
  127. Rice TW, Wheeler AP, Bernard GR, et al. Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest 2007; 132:410.
  128. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818.
  129. Schwarz MI, Albert RK. “Imitators” of the ARDS: implications for diagnosis and treatment. Chest 2004; 125:1530.
  130. Pope-Harman AL, Davis WB, Allen ED, et al. Acute eosinophilic pneumonia. A summary of 15 cases and review of the literature. Medicine (Baltimore) 1996; 75:334.
  131. Buchheit J, Eid N, Rodgers G Jr, et al. Acute eosinophilic pneumonia with respiratory failure: a new syndrome? Am Rev Respir Dis 1992; 145:716.
  132. Philit F, Etienne-Mastroïanni B, Parrot A, et al. Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med 2002; 166:1235.
  133. MacCallum NS, Evans TW. Epidemiology of acute lung injury. Curr Opin Crit Care 2005; 11:43.
  134. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353:1685.
  135. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351:327.
  136. Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome. Crit Care Med 2002; 30:2450.
  137. Bersten AD, Edibam C, Hunt T, et al. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002; 165:443.
  138. Villar J, Blanco J, Añón JM, et al. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011; 37:1932.
  139. Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485.
  140. Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death in patients with ARDS. Chest 2005; 128:525.
  141. Erickson SE, Martin GS, Davis JL, et al. Recent trends in acute lung injury mortality: 1996-2005. Crit Care Med 2009; 37:1574.
  142. Zambon M, Vincent JL. Mortality rates for patients with acute lung injury/ARDS have decreased over time. Chest 2008; 133:1120.
  143. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301.
  144. The ARDS Definition Task Force. Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA 2012; May 21:Epub ahead of print.
  145. Bone RC, Maunder R, Slotman G, et al. An early test of survival in patients with the adult respiratory distress syndrome. The PaO2/FIo2 ratio and its differential response to conventional therapy. Prostaglandin E1 Study Group. Chest 1989; 96:849.
  146. Bull TM, Clark B, McFann K, et al. Pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury. Am J Respir Crit Care Med 2010; 182:1123.
  147. Nuckton TJ, Alonso JA, Kallet RH, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002; 346:1281.
  148. Doyle RL, Szaflarski N, Modin GW, et al. Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818.
  149. Bone RC, Balk R, Slotman G, et al. Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. The Prostaglandin E1 Study Group. Chest 1992; 101:320.
  150. Suchyta MR, Clemmer TP, Elliott CG, et al. The adult respiratory distress syndrome. A report of survival and modifying factors. Chest 1992; 101:1074.
  151. Sloane PJ, Gee MH, Gottlieb JE, et al. A multicenter registry of patients with acute respiratory distress syndrome. Physiology and outcome. Am Rev Respir Dis 1992; 146:419.
  152. Headley AS, Tolley E, Meduri GU. Infections and the inflammatory response in acute respiratory distress syndrome. Chest 1997; 111:1306.
  153. Ely EW, Wheeler AP, Thompson BT, et al. Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med 2002; 136:25.
  154. Levitt JE, Gould MK, Ware LB, Matthay MA. The pathogenetic and prognostic value of biologic markers in acute lung injury. J Intensive Care Med 2009; 24:151.
  155. Sakr Y, Vincent JL, Reinhart K, et al. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest 2005; 128:3098.
  156. Rosenberg AL, Dechert RE, Park PK, et al. Review of a large clinical series: association of cumulative fluid balance on outcome in acute lung injury: a retrospective review of the ARDSnet tidal volume study cohort. J Intensive Care Med 2009; 24:35.
  157. Netzer G, Shah CV, Iwashyna TJ, et al. Association of RBC transfusion with mortality in patients with acute lung injury. Chest 2007; 132:1116.
  158. Treggiari MM, Martin DP, Yanez ND, et al. Effect of intensive care unit organizational model and structure on outcomes in patients with acute lung injury. Am J Respir Crit Care Med 2007; 176:685.
  159. Elliott CG, Morris AH, Cengiz M. Pulmonary function and exercise gas exchange in survivors of adult respiratory distress syndrome. Am Rev Respir Dis 1981; 123:492.
  160. Neff TA, Stocker R, Frey HR, et al. Long-term assessment of lung function in survivors of severe ARDS. Chest 2003; 123:845.
  161. Orme J Jr, Romney JS, Hopkins RO, et al. Pulmonary function and health-related quality of life in survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 2003; 167:690.
  162. Suchyta MR, Elliott CG, Jensen RL, Crapo RO. Predicting the presence of pulmonary function impairment in adult respiratory distress syndrome survivors. Respiration 1993; 60:103.
  163. McHugh LG, Milberg JA, Whitcomb ME, et al. Recovery of function in survivors of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1994; 150:90.
  164. Cheung AM, Tansey CM, Tomlinson G, et al. Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 174:538.
  165. Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364:1293.
  166. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003; 348:683.
  167. Angus DC, Musthafa AA, Clermont G, et al. Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 163:1389.
  168. Hopkins RO, Weaver LK, Collingridge D, et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005; 171:340.
  169. Hopkins RO, Weaver LK, Pope D, et al. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160:50.
  170. Cox CE, Docherty SL, Brandon DH, et al. Surviving critical illness: acute respiratory distress syndrome as experienced by patients and their caregivers. Crit Care Med 2009; 37:2702.
  171. Bienvenu OJ, Colantuoni E, Mendez-Tellez PA, et al. Depressive symptoms and impaired physical function after acute lung injury: a 2-year longitudinal study. Am J Respir Crit Care Med 2012; 185:517.
  172. Mikkelsen ME, Christie JD, Lanken PN, et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 2012; 185:1307.
  173. Elliott CG, Rasmusson BY, Crapo RO, et al. Prediction of pulmonary function abnormalities after adult respiratory distress syndrome (ARDS). Am Rev Respir Dis 1987; 135:634.
  174. Ghio AJ, Elliott CG, Crapo RO, et al. Impairment after adult respiratory distress syndrome. An evaluation based on American Thoracic Society recommendations. Am Rev Respir Dis 1989; 139:1158.
  175. Cooper AB, Ferguson ND, Hanly PJ, et al. Long-term follow-up of survivors of acute lung injury: lack of effect of a ventilation strategy to prevent barotrauma. Crit Care Med 1999; 27:2616.
  176. Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death in patients with ARDS. Chest 2005; 128:525.
  177. Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485.
  178. Suchyta MR, Clemmer TP, Elliott CG, et al. The adult respiratory distress syndrome. A report of survival and modifying factors. Chest 1992; 101:1074.
  179. Doyle RL, Szaflarski N, Modin GW, et al. Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818.
  180. Hansen-Flaschen J. Improving patient tolerance of mechanical ventilation. Challenges ahead. Crit Care Clin 1994; 10:659.
  181. Swinamer DL, Phang PT, Jones RL, et al. Effect of routine administration of analgesia on energy expenditure in critically ill patients. Chest 1988; 93:4.
  182. Cernaianu AC, DelRossi AJ, Flum DR, et al. Lorazepam and midazolam in the intensive care unit: a randomized, prospective, multicenter study of hemodynamics, oxygen transport, efficacy, and cost. Crit Care Med 1996; 24:222.
  183. Stoltzfus DP. Advantages and disadvantages of combining sedative agents. Crit Care Clin 1995; 11:903.
  184. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30:119.
  185. Mirenda J, Broyles G. Propofol as used for sedation in the ICU. Chest 1995; 108:539.
  186. Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994; 22:433.
  187. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471.
  188. Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114:541.
  189. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166:1338.
  190. Cheng IW, Eisner MD, Thompson BT, et al. Acute effects of tidal volume strategy on hemodynamics, fluid balance, and sedation in acute lung injury. Crit Care Med 2005; 33:63.
  191. Kahn JM, Andersson L, Karir V, et al. Low tidal volume ventilation does not increase sedation use in patients with acute lung injury. Crit Care Med 2005; 33:766.
  192. Sud S, Friedrich JO, Taccone P, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med 2010; 36:585.
  193. Gainnier M, Roch A, Forel JM, et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med 2004; 32:113.
  194. Watling SM, Dasta JF. Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature. Crit Care Med 1994; 22:884.
  195. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010; 363:1107.
  196. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010; 363:1107.
  197. Cerra FB, Benitez MR, Blackburn GL, et al. Applied nutrition in ICU patients. A consensus statement of the American College of Chest Physicians. Chest 1997; 111:769.
  198. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet 1999; 354:1851.
  199. Delclaux C, Roupie E, Blot F, et al. Lower respiratory tract colonization and infection during severe acute respiratory distress syndrome: incidence and diagnosis. Am J Respir Crit Care Med 1997; 156:1092.
  200. Fagon JY, Chastre J, Hance AJ, et al. Evaluation of clinical judgment in the identification and treatment of nosocomial pneumonia in ventilated patients. Chest 1993; 103:547.
  201. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388.
  202. Lin CC, Lin CY. Enhanced chemiluminescence with decreased antibody-dependent cellular cytotoxicity of human alveolar neutrophil in patients with adult respiratory distress syndrome. Respiration 1992; 59:265.
  203. Kollef MH. Prevention of hospital-associated pneumonia and ventilator-associated pneumonia. Crit Care Med 2004; 32:1396.
  204. Verwaest C, Verhaegen J, Ferdinande P, et al. Randomized, controlled trial of selective digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med 1997; 25:63.
  205. Vallés J, Artigas A, Rello J, et al. Continuous aspiration of subglottic secretions in preventing ventilator-associated pneumonia. Ann Intern Med 1995; 122:179.
  206. Siempos II, Vardakas KZ, Falagas ME. Closed tracheal suction systems for prevention of ventilator-associated pneumonia. Br J Anaesth 2008; 100:299.
  207. Schuster DP, Rowley H, Feinstein S, et al. Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984; 76:623.
  208. Hasleton PS. Adult respiratory distress syndrome. In: Spencer’s Pathology of the Lung, Hasleton PS (Ed), McGraw Hill, New York 1996. p.375.
  209. Wagner PD, Laravuso RB, Uhl RR, West JB. Continuous distributions of ventilation-perfusion ratios in normal subjects breathing air and 100 per cent O2. J Clin Invest 1974; 54:54.
  210. Santos C, Ferrer M, Roca J, et al. Pulmonary gas exchange response to oxygen breathing in acute lung injury. Am J Respir Crit Care Med 2000; 161:26.
  211. Sackner MA, Landa J, Hirsch J, Zapata A. Pulmonary effects of oxygen breathing. A 6-hour study in normal men. Ann Intern Med 1975; 82:40.
  212. Comroe, JH, Dripps, RD, Dumke, PR, et al. The effect of inhalation of high concentrations of oxygen for 24 hours on normal men at sea level and at a simulated altitude of 18,000. JAMA 1945; 128:710.
  213. Freeman BA, Crapo JD. Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. J Biol Chem 1981; 256:10986.
  214. Lodato RF. Oxygen toxicity. In: Principles and Practice of Mechanical Ventilation, Tobin MJ (Ed), McGraw-Hill Inc, New York 1994. p.837.
  215. Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery catheterization. Am Rev Respir Dis 1992; 145:990.
  216. Simmons RS, Berdine GG, Seidenfeld JJ, et al. Fluid balance and the adult respiratory distress syndrome. Am Rev Respir Dis 1987; 135:924.
  217. Humphrey H, Hall J, Sznajder I, et al. Improved survival in ARDS patients associated with a reduction in pulmonary capillary wedge pressure. Chest 1990; 97:1176.
  218. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354:2564.
  219. Martin GS, Mangialardi RJ, Wheeler AP, et al. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med 2002; 30:2175.
  220. Suzuki S, Hotchkiss JR, Takahashi T, et al. Effect of core body temperature on ventilator-induced lung injury. Crit Care Med 2004; 32:144.
  221. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340:409.
  222. Gong MN, Thompson BT, Williams P, et al. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 2005; 33:1191.
  223. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 1995; 333:1025.
  224. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330:1717.
  225. Weg JG, Balk RA, Tharratt RS, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome. JAMA 1994; 272:1433.
  226. Spragg RG, Lewis JF, Wurst W, et al. Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant. Am J Respir Crit Care Med 2003; 167:1562.
  227. Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med 1996; 334:1417.
  228. Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004; 351:884.
  229. Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1997; 155:1309.
  230. Davidson WJ, Dorscheid D, Spragg R, et al. Exogenous pulmonary surfactant for the treatment of adult patients with acute respiratory distress syndrome: results of a meta-analysis. Crit Care 2006; 10:R41.
  231. Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA 2005; 293:470.
  232. Calfactant for Direct Acute Respiratory Distress Syndrome (CARDS) http://clinicaltrials.gov/show/NCT00682500 (Accessed on February 07, 2012).
  233. Kerr CL, Ito Y, Manwell SE, et al. Effects of surfactant distribution and ventilation strategies on efficacy of exogenous surfactant. J Appl Physiol 1998; 85:676.
  234. Ito Y, Manwell SE, Kerr CL, et al. Effects of ventilation strategies on the efficacy of exogenous surfactant therapy in a rabbit model of acute lung injury. Am J Respir Crit Care Med 1998; 157:149.
  235. Albert RK. The role of ventilation-induced surfactant dysfunction and atelectasis in causing acute respiratory distress syndrome. Am J Respir Crit Care Med 2012; 185:702.
  236. Taut FJ, Rippin G, Schenk P, et al. A Search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a pooled analysis of five studies with recombinant surfactant protein-C surfactant (Venticute). Chest 2008; 134:724.
  237. Spragg RG, Taut FJ, Lewis JF, et al. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. Am J Respir Crit Care Med 2011; 183:1055.
  238. Zimmerman JJ. Surfactant is a target during acute lung injury inflammation. Crit Care Med 1996; 24:916.
  239. Hallman M, Spragg R, Harrell JH, et al. Evidence of lung surfactant abnormality in respiratory failure. Study of bronchoalveolar lavage phospholipids, surface activity, phospholipase activity, and plasma myoinositol. J Clin Invest 1982; 70:673.
  240. Gregory, TJ, Longmore, WJ, Moxley, MA, et al. Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J Clin Invest 1991; 88:1976.
  241. Quinlan GJ, Lamb NJ, Tilley R, et al. Plasma hypoxanthine levels in ARDS: implications for oxidative stress, morbidity, and mortality. Am J Respir Crit Care Med 1997; 155:479.
  242. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med 1999; 27:1409.
  243. Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006; 34:1033.
  244. Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 2011; 306:1574.
  245. Stapleton RD, Martin TR, Weiss NS, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Crit Care Med 2011; 39:1655.
  246. Bursten SL, Federighi DA, Parsons P, et al. An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. Crit Care Med 1996; 24:1129.
  247. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med 2002; 30:1.
  248. Laurent T, Markert M, Feihl F, et al. Oxidant-antioxidant balance in granulocytes during ARDS. Effect of N-acetylcysteine. Chest 1996; 109:163.
  249. Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest 1997; 112:164.
  250. Jepsen S, Herlevsen P, Knudsen P, et al. Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study. Crit Care Med 1992; 20:918.
  251. Paine R 3rd, Standiford TJ, Dechert RE, et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med 2012; 40:90.
  252. Matute-Bello G, Liles WC, Radella F 2nd, et al. Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med 2000; 28:1.
  253. Paine R 3rd, Wilcoxen SE, Morris SB, et al. Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury. Am J Pathol 2003; 163:2397.
  254. Baleeiro CE, Christensen PJ, Morris SB, et al. GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress. Am J Physiol Lung Cell Mol Physiol 2006; 291:L1246.
  255. Rossaint R, Falke KJ, López F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328:399.
  256. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004; 291:1603.
  257. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 1998; 26:15.
  258. Adhikari NK, Burns KE, Friedrich JO, et al. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 2007; 334:779.
  259. Afshari A, Brok J, Møller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: a systematic review with meta-analysis and trial sequential analysis. Anesth Analg 2011; 112:1411.
  260. Pipeling MR, Fan E. Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA 2010; 304:2521.
  261. Rossaint R, Gerlach H, Schmidt-Ruhnke H, et al. Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest 1995; 107:1107.
  262. Manktelow C, Bigatello LM, Hess D, Hurford WE. Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 1997; 87:297.
  263. Puybasset L, Rouby JJ, Mourgeon E, et al. Factors influencing cardiopulmonary effects of inhaled nitric oxide in acute respiratory failure. Am J Respir Crit Care Med 1995; 152:318.
  264. Puri N, Dellinger RP. Inhaled nitric oxide and inhaled prostacyclin in acute respiratory distress syndrome: what is the evidence? Crit Care Clin 2011; 27:561.
  265. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 2005; 353:2683.
  266. Afshari A, Brok J, Møller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev 2010; :CD002787.
  267. Zwissler B, Kemming G, Habler O, et al. Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome. Am J Respir Crit Care Med 1996; 154:1671.
  268. Walmrath D, Schneider T, Schermuly R, et al. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 153:991.
  269. Ferring M, Vincent JL. Is outcome from ARDS related to the severity of respiratory failure? Eur Respir J 1997; 10:1297.
  270. Royston D. Inhalational agents for pulmonary hypertension. Lancet 1993; 342:941.
  271. van Heerden PV, Barden A, Michalopoulos N, et al. Dose-response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest 2000; 117:819.
  272. Domenighetti G, Stricker H, Waldispuehl B. Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response. Crit Care Med 2001; 29:57.
  273. Afshari A, Brok J, Møller AM, Wetterslev J. Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Cochrane Database Syst Rev 2010; :CD007733.
  274. Steinberg KP, Milberg JA, Martin TR, et al. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med 1994; 150:113.
  275. Davis WB, Wilson HE, Wall RL. Eosinophilic alveolitis in acute respiratory failure. A clinical marker for a non-infectious etiology. Chest 1986; 90:7.
  276. Tang BM, Craig JC, Eslick GD, et al. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med 2009; 37:1594.
  277. Meduri GU, Marik PE, Chrousos GP, et al. Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature. Intensive Care Med 2008; 34:61.
  278. Agarwal R, Nath A, Aggarwal AN, Gupta D. Do glucocorticoids decrease mortality in acute respiratory distress syndrome? A meta-analysis. Respirology 2007; 12:585.
  279. Peter JV, John P, Graham PL, et al. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ 2008; 336:1006.
  280. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354:1671.
  281. Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007; 131:954.
  282. Craig TR, Duffy MJ, Shyamsundar M, et al. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med 2011; 183:620.
  283. Simvastatin Effect on the Incidence of Acute Lung Injury/Adult Respiratory Distress Syndrome (ALI/ARDS) http://www.clinicaltrials.gov/ct2/show/NCT01195428 (Accessed on February 08, 2012).
  284. Kawashima M, yatsunami J, Fukuno Y, et al. Inhibitory effects of 14-membered ring macrolide antibiotics on bleomycin-induced acute lung injury. Lung 2002; 180:73.
  285. Leiva M, Ruiz-Bravo A, Jimenez-Valera M. Effects of telithromycin in in vitro and in vivo models of lipopolysaccharide-induced airway inflammation. Chest 2008; 134:20.
  286. Walkey AJ, Wiener RS. Macrolide antibiotics and survival in patients with acute lung injury. Chest 2012; 141:1153.
  287. Sakuma T, Okaniwa G, Nakada T, et al. Alveolar fluid clearance in the resected human lung. Am J Respir Crit Care Med 1994; 150:305.
  288. Sakuma T, Suzuki S, Usuda K, et al. Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe hypothermia. J Appl Physiol 1996; 80:1681.
  289. Sartori C, Allemann Y, Duplain H, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002; 346:1631.
  290. Perkins GD, Gao F, Thickett DR. In vivo and in vitro effects of salbutamol on alveolar epithelial repair in acute lung injury. Thorax 2008; 63:215.
  291. Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 2006; 173:281.
  292. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Matthay MA, Brower RG, et al. Randomized, placebo-controlled clinical trial of an aerosolized β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011; 184:561.
  293. Gao Smith F, Perkins GD, Gates S, et al. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012; 379:229.
  294. Bone RC, Slotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Prostaglandin E1 Study Group. Chest 1989; 96:114.
  295. Abraham E, Baughman R, Fletcher E, et al. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group. Crit Care Med 1999; 27:1478.
  296. Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med 2004; 32:1695.
  297. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 1997; 336:912.
  298. Liu KD, Levitt J, Zhuo H, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008; 178:618.
  299. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network. JAMA 2000; 283:1995.
  300. Slotman GJ, Burchard KW, D’Arezzo A, Gann DS. Ketoconazole prevents acute respiratory failure in critically ill surgical patients. J Trauma 1988; 28:648.
  301. Yu M, Tomasa G. A double-blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome. Crit Care Med 1993; 21:1635.
  302. Sinuff T, Cook DJ, Peterson JC, Fuller HD. Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS prophylaxis. J Crit Care 1999; 14:1.
  303. Williams JG, Maier RV. Ketoconazole inhibits alveolar macrophage production of inflammatory mediators involved in acute lung injury (adult respiratory distress syndrome). Surgery 1992; 112:270.
  304. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301.
  305. Petrucci N, Iacovelli W. Ventilation with lower tidal volumes versus traditional tidal volumes in adults for acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev 2004; :CD003844.
  306. Putensen C, Theuerkauf N, Zinserling J, et al. Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009; 151:566.
  307. Needham DM, Colantuoni E, Mendez-Tellez PA, et al. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study. BMJ 2012; 344:e2124.
  308. Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER. Hypercapnic acidosis and mortality in acute lung injury. Crit Care Med 2006; 34:1.
  309. de Durante G, del Turco M, Rustichini L, et al. ARDSNet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 165:1271.
  310. Hough CL, Kallet RH, Ranieri VM, et al. Intrinsic positive end-expiratory pressure in Acute Respiratory Distress Syndrome (ARDS) Network subjects. Crit Care Med 2005; 33:527.
  311. Kallet RH, Campbell AR, Dicker RA, et al. Effects of tidal volume on work of breathing during lung-protective ventilation in patients with acute lung injury and acute respiratory distress syndrome. Crit Care Med 2006; 34:8.
  312. Kahn JM, Andersson L, Karir V, et al. Low tidal volume ventilation does not increase sedation use in patients with acute lung injury. Crit Care Med 2005; 33:766.
  313. Pohlman MC, McCallister KE, Schweickert WD, et al. Excessive tidal volume from breath stacking during lung-protective ventilation for acute lung injury. Crit Care Med 2008; 36:3019.
  314. Terragni PP, Rosboch G, Tealdi A, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007; 175:160.
  315. Chiumello D, Carlesso E, Cadringher P, et al. Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med 2008; 178:346.
  316. Hager DN, Krishnan JA, Hayden DL, et al. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005; 172:1241.
  317. Umoh NJ, Fan E, Mendez-Tellez PA, et al. Patient and intensive care unit organizational factors associated with low tidal volume ventilation in acute lung injury. Crit Care Med 2008; 36:1463.
  318. Richecoeur J, Lu Q, Vieira SR, et al. Expiratory washout versus optimization of mechanical ventilation during permissive hypercapnia in patients with severe acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160:77.
  319. Prin S, Chergui K, Augarde R, et al. Ability and safety of a heated humidifier to control hypercapnic acidosis in severe ARDS. Intensive Care Med 2002; 28:1756.
  320. Broccard AF, Hotchkiss JR, Vannay C, et al. Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med 2001; 164:802.
  321. Sinclair SE, Kregenow DA, Lamm WJ, et al. Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 2002; 166:403.
  322. Broccard AF. Respiratory acidosis and acute respiratory distress syndrome: time to trade in a bull market? Crit Care Med 2006; 34:229.
  323. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347.
  324. Villar J, Kacmarek RM, Pérez-Méndez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 2006; 34:1311.
  325. Huh JW, Jung H, Choi HS, et al. Efficacy of positive end-expiratory pressure titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress syndrome. Crit Care 2009; 13:R22.
  326. Gattinoni L, Pelosi P, Crotti S, Valenza F. Effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151:1807.
  327. Malbouisson LM, Muller JC, Constantin JM, et al. Computed tomography assessment of positive end-expiratory pressure-induced alveolar recruitment in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 163:1444.
  328. Ranieri VM, Eissa NT, Corbeil C, et al. Effects of positive end-expiratory pressure on alveolar recruitment and gas exchange in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1991; 144:544.
  329. Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008; 299:646.
  330. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008; 299:637.
  331. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010; 303:865.
  332. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006; 354:1775.
  333. Slutsky AS, Hudson LD. PEEP or no PEEP–lung recruitment may be the solution. N Engl J Med 2006; 354:1839.
  334. Caironi P, Cressoni M, Chiumello D, et al. Lung opening and closing during ventilation of acute respiratory distress syndrome. Am J Respir Crit Care Med 2010; 181:578.
  335. Fougères E, Teboul JL, Richard C, et al. Hemodynamic impact of a positive end-expiratory pressure setting in acute respiratory distress syndrome: importance of the volume status. Crit Care Med 2010; 38:802.
  336. Brower RG, Morris A, MacIntyre N, et al. Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure. Crit Care Med 2003; 31:2592.
  337. Halter JM, Steinberg JM, Schiller HJ, et al. Positive end-expiratory pressure after a recruitment maneuver prevents both alveolar collapse and recruitment/derecruitment. Am J Respir Crit Care Med 2003; 167:1620.
  338. Lim CM, Jung H, Koh Y, et al. Effect of alveolar recruitment maneuver in early acute respiratory distress syndrome according to antiderecruitment strategy, etiological category of diffuse lung injury, and body position of the patient. Crit Care Med 2003; 31:411.
  339. Fan E, Wilcox ME, Brower RG, et al. Recruitment maneuvers for acute lung injury: a systematic review. Am J Respir Crit Care Med 2008; 178:1156.
  340. Hodgson C, Keating JL, Holland AE, et al. Recruitment manoeuvres for adults with acute lung injury receiving mechanical ventilation. Cochrane Database Syst Rev 2009; :CD006667.
  341. Richard JC, Maggiore SM, Jonson B, et al. Influence of tidal volume on alveolar recruitment. Respective role of PEEP and a recruitment maneuver. Am J Respir Crit Care Med 2001; 163:1609.
  342. Arnal JM, Paquet J, Wysocki M, et al. Optimal duration of a sustained inflation recruitment maneuver in ARDS patients. Intensive Care Med 2011; 37:1588.
  343. Crotti S, Mascheroni D, Caironi P, et al. Recruitment and derecruitment during acute respiratory failure: a clinical study. Am J Respir Crit Care Med 2001; 164:131.
  344. Bugedo G, Bruhn A, Hernández G, et al. Lung computed tomography during a lung recruitment maneuver in patients with acute lung injury. Intensive Care Med 2003; 29:218.
  345. Foti G, Cereda M, Sparacino ME, et al. Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated acute respiratory distress syndrome (ARDS) patients. Intensive Care Med 2000; 26:501.
  346. Jonson B, Richard JC, Straus C, et al. Pressure-volume curves and compliance in acute lung injury: evidence of recruitment above the lower inflection point. Am J Respir Crit Care Med 1999; 159:1172.
  347. Maggiore SM, Lellouche F, Pigeot J, et al. Prevention of endotracheal suctioning-induced alveolar derecruitment in acute lung injury. Am J Respir Crit Care Med 2003; 167:1215.
  348. Pelosi P, Cadringher P, Bottino N, et al. Sigh in acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 159:872.
  349. Pelosi P, Bottino N, Chiumello D, et al. Sigh in supine and prone position during acute respiratory distress syndrome. Am J Respir Crit Care Med 2003; 167:521.
  350. Ranieri VM, Brienza N, Santostasi S, et al. Impairment of lung and chest wall mechanics in patients with acute respiratory distress syndrome: role of abdominal distension. Am J Respir Crit Care Med 1997; 156:1082.
  351. Puybasset L, Gusman P, Muller JC, et al. Regional distribution of gas and tissue in acute respiratory distress syndrome. III. Consequences for the effects of positive end-expiratory pressure. CT Scan ARDS Study Group. Adult Respiratory Distress Syndrome. Intensive Care Med 2000; 26:1215.
  352. Zhan Q, Sun B, Liang L, et al. Early use of noninvasive positive pressure ventilation for acute lung injury: a multicenter randomized controlled trial. Crit Care Med 2012; 40:455.
  353. Marcy TW, Marini JJ. Inverse ratio ventilation in ARDS. Rationale and implementation. Chest 1991; 100:494.
  354. Marcy TW. Inverse ratio ventilation. In: Principles and Practice of Mechanical Ventilation, Tobin MJ (Ed), McGraw-Hill Inc, New York 1994. p.319.
  355. Armstrong BW Jr, MacIntyre NR. Pressure-controlled, inverse ratio ventilation that avoids air trapping in the adult respiratory distress syndrome. Crit Care Med 1995; 23:279.
  356. Mercat A, Titiriga M, Anguel N, et al. Inverse ratio ventilation (I/E = 2/1) in acute respiratory distress syndrome: a six-hour controlled study. Am J Respir Crit Care Med 1997; 155:1637.
  357. Ward NS, Lin DY, Nelson DL, et al. Successful determination of lower inflection point and maximal compliance in a population of patients with acute respiratory distress syndrome. Crit Care Med 2002; 30:963.
  358. Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008; 359:2095.
  359. Bernard GR. PEEP guided by esophageal pressure–any added value? N Engl J Med 2008; 359:2166.
  360. Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149:1327.
  361. Mancebo J. PEEP, ARDS, and alveolar recruitment. Intensive Care Med 1992; 18:383.
  362. Dreyfuss D, Saumon G. Should the lung be rested or recruited? The Charybdis and Scylla of ventilator management. Am J Respir Crit Care Med 1994; 149:1066.
  363. Suter PM, Fairley B, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975; 292:284.
  364. Dambrosio M, Roupie E, Mollet JJ, et al. Effects of positive end-expiratory pressure and different tidal volumes on alveolar recruitment and hyperinflation. Anesthesiology 1997; 87:495.
  365. Decailliot F, Demoule A, Maggiore SM, et al. Pressure-volume curves with and without muscle paralysis in acute respiratory distress syndrome. Intensive Care Med 2006; 32:1322.
  366. Gattinoni L, D’Andrea L, Pelosi P, et al. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 1993; 269:2122.
  367. Maggiore SM, Jonson B, Richard JC, et al. Alveolar derecruitment at decremental positive end-expiratory pressure levels in acute lung injury: comparison with the lower inflection point, oxygenation, and compliance. Am J Respir Crit Care Med 2001; 164:795.
  368. Mergoni M, Martelli A, Volpi A, et al. Impact of positive end-expiratory pressure on chest wall and lung pressure-volume curve in acute respiratory failure. Am J Respir Crit Care Med 1997; 156:846.
  369. O’Keefe GE, Gentilello LM, Erford S, Maier RV. Imprecision in lower “inflection point” estimation from static pressure-volume curves in patients at risk for acute respiratory distress syndrome. J Trauma 1998; 44:1064.
  370. Grasso S, Stripoli T, De Michele M, et al. ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir Crit Care Med 2007; 176:761.
  371. Lu Q, Vieira SR, Richecoeur J, et al. A simple automated method for measuring pressure-volume curves during mechanical ventilation. Am J Respir Crit Care Med 1999; 159:275.
  372. Albert RK. Least PEEP: primum non nocere. Chest 1985; 87:2.
  373. Bouhemad B, Brisson H, Le-Guen M, et al. Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment. Am J Respir Crit Care Med 2011; 183:341.
  374. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010; 363:1107.

2 thoughts on “ARDS

  1. Pingback: ARDS | Welcome to Jeremy Jaramillo's Blog

  2. Pingback: Obesity Hypoventilation Syndrome | Welcome to Jeremy Jaramillo's Blog

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