Acute respiratory distress syndrome (ARDS) is an acute, diffuse, inflammatory injury to the alveolar epithelium and pulmonary vascular endothelium that leads to nonhydrostatic pulmonary edema and impaired pulmonary gas exchange. ARDS is difficult to define clinically because it represents a constellation of individually nonspecific findings triggered by a wide range of precipitating insults to the lung. Still, a reproducible definition of ARDS is essential to consistently identify patients with a similar phenotype for research and clinical care.
In clinical trials and other studies, a homogeneous population sample minimizes pathophysiologic variability; this minimization is important because distinct subphenotypes may carry different prognoses and respond differently to therapies. It also allows for comparison of research findings and epidemiologic data across studies. For patient care, a standardized definition promotes evidence-based management and prognostication by allowing comparison of each patient to research study participants.
Although ARDS was first described by Ashbaugh et al. in 1967, no consensus definition existed until the 1994 American-European Consensus Conference (AECC) on ARDS. The updated consensus Berlin definition was put forth in 2012. Although the Berlin definition performs better in several respects, recent evidence suggests that substantial biological, pathologic, and clinical heterogeneity remains within this broad definition of ARDS.
Five Decades of Defining ARDS
Recognizing ARDS as a Clinical Entity
Five decades ago, Ashbaugh and colleagues first identified ARDS as a common lung injury response to various insults—multiple trauma, lung contusion, pancreatitis, toxic ingestion, and pneumonia—that did not respond to usual respiratory support. Their series of 12 patients established the salient features of ARDS that have served as the foundation for all subsequent definitions: the acute onset of hypoxemia and bilateral infiltrates on chest radiograph that are not entirely due to heart failure. Decreased respiratory system compliance (C RS ) was common to all included patients. Postmortem histologic examination demonstrated intra-alveolar edema and hyaline membranes in most patients who died early in their course and diffuse interstitial inflammation and fibrosis in patients who died after a protracted course.
After the seminal article by Ashbaugh et al., ARDS gained widespread recognition as an important clinical entity. However, a specific consensus definition remained elusive. In 1988, Murray and colleagues proposed perhaps the most widely recognized diagnostic criteria for ARDS before a consensus definition. Their Lung Injury Score awards points for severity of derangement in four clinical factors: hypoxemia (partial pressure of oxygen in arterial blood [Pa o 2 ]/fraction of inspired oxygen [F io 2 ]), chest radiographic opacities (number of quadrants), positive end-expiratory pressure (PEEP) level, and C RS . A numeric cutoff was proposed to define ARDS. Importantly, Murray and colleagues also recommended expanding their score-based definition to describe the time course since ARDS onset (acute or chronic phase) and underlying risk factor(s) (e.g., aspiration, sepsis). Both additions informally addressed prognostic and treatment implications of different phases and causes of ARDS.
Achieving Consensus on Defining ARDS
The 1994 AECC definition represented the first international consensus on how to define ARDS. Under the auspices of the American Thoracic Society and the European Society of Intensive Care Medicine, an expert panel was convened to establish diagnostic criteria for ARDS with the primary stated intent of enhancing research coordination and collaboration to more efficiently advance therapeutic investigation.
The expert panel considered timing of onset, oxygenation, chest radiograph findings, and absence of hydrostatic pulmonary edema as the defining features of ARDS. Specifically, they defined ARDS as the acute onset of impaired oxygenation with a Pa o 2 /F io 2 of 200 mm Hg or less accompanied by bilateral infiltrates on frontal chest radiograph and a pulmonary artery wedge pressure (PAWP) of 18 mm Hg or less (if measured) or no clinical evidence of left atrial hypertension. The AECC separately defined acute lung injury (ALI) as having a Pa o 2 /F io 2 of 300 mm Hg or less while meeting all other criteria for ARDS. That is, ALI represented a broader spectrum of lung injury that included ARDS on the severe end of the spectrum. The decision to distinguish ARDS as the severe form of ALI stemmed from concern that processes other than ARDS that are associated with impaired gas exchange were likelier to be included under a more liberal threshold.
In addition to the benefits of consensus per se, the AECC definition offered several strengths. The definition was applicable to the research, epidemiology, and individual patient care settings, aiding cross-study comparison and translation of study findings to clinical practice. In addition, specific criteria for oxygenation (Pa o 2 /F io 2 ) and radiographic findings were established, attempting to address substantial sources of heterogeneity in the literature at the time. The expert panel also recognized that lung injury occurs on a continuum of oxygenation and chest radiographic abnormalities, acknowledging that the specific thresholds chosen were in a sense arbitrary.
However, important limitations to the AECC definition became increasingly evident on its widespread adoption. Acuity of onset was not explicitly defined. Oxygenation criteria did not address the impact of PEEP, F io 2 , and other ventilator settings on Pa o 2 /F io 2 . Even among expert intensivists and radiologists, poor interobserver agreement in applying the AECC radiographic criteria for ARDS was demonstrated. Finally, without accounting for the substantial variation in duration and intensity of exposure to lung injury triggers, the resultant heterogeneous patient population may exhibit a range of prognoses and responses to therapy. Perhaps because of these issues, clinical diagnosis of ARDS applying the AECC definition was shown to have only moderate sensitivity and specificity in the identification of diffuse alveolar damage on pathologic examination. An updated definition was sought so that these limitations could be addressed and an advanced understanding of ARDS pathophysiology could be incorporated.
2012 Berlin Definition
The European Society of Intensive Care Medicine, with the endorsement of the American Thoracic Society and Society of Critical Care Medicine, convened an international expert panel to revise the previous AECC definition by incorporating the wealth of evidence that accumulated after the AECC definition ( Table 28-1 ). The Berlin consensus conference updated each of the elements included from the AECC definition: timing, chest radiographic findings, origin of edema, and oxygenation. It also systematically evaluated other variables proposed to predict clinical outcomes in ARDS in an attempt to establish predictive validity. Individual patient-level meta-analysis of 4188 patients pooled from four multicenter and three single-center datasets of patients with ARDS was used to consider ancillary variables for inclusion in the updated definition to determine if these variables enhanced predictive validity without adding unnecessary complexity or jeopardizing feasibility.
| Timing | Within 1 week of a known clinical insult or new or worsening respiratory symptoms |
| Chest imaging | Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules |
| Origin of edema | Respiratory failure not fully explained by cardiac failure or fluid overload Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present |
| Oxygenation | |
| Mild | 200 mm Hg < Pa o 2 /F io 2 ≤ 300 mm Hg with PEEP or CPAP ≥ 5 cm H 2 O |
| Moderate | 100 mm Hg < Pa o 2 /F io 2 ≤ 200 mm Hg with PEEP ≥ 5 cm H 2 O |
| Severe | Pa o 2 /F io 2 ≤ 100 mm Hg with PEEP ≥ 5 cm H 2 O |
Acuity of Onset
The AECC definition lacked specific criteria to describe acuity of onset. Several epidemiologic studies have shown that most cases of ARDS develop within the first 72 hours of hospitalization when a predisposing condition is present on admission. In a 22-hospital cohort of 5584 patients at risk of ARDS on hospital admission, Gajic et al. found that ARDS developed a median of 2 days after hospitalization (interquartile range, 1 to 4 days). Other studies have found that over half of ARDS cases occur within 24 hours of hospitalization when a risk factor is present on admission. Virtually all cases occur within 7 days after an identifiable risk factor occurs, regardless of the mechanism. To incorporate these findings, the Berlin definition newly requires that timing of onset be within 1 week of a known clinical insult or new or worsening respiratory symptoms.
Oxygenation
For the confusion around the related AECC definitions of ALI and ARDS to be addressed, the term ALI was removed from the updated Berlin definition. In turn, ARDS was classified into three categories depending on severity of impaired oxygenation: mild (Pa o 2 /F io 2 201 to 300 mm Hg with PEEP or continuous positive airway pressure [CPAP] ≥5 cm H 2 O), moderate (Pa o 2 /F io 2 101 to 200 mm Hg with PEEP ≥5 cm H 2 O), and severe (Pa o 2 /F io 2 ≤ 100 mm Hg with PEEP ≥5 cm H 2 O). The inclusion of a separate category for severe ARDS was influenced by recent clinical trials that tested interventions only in the subset of patients with more severe ARDS. The prognostic utility of Pa o 2 /F io 2 thresholds for mild, moderate, and severe ARDS was confirmed by individual patient-level meta-analysis: mortality was 27% (95% confidence interval [CI], 24% to 30%) for mild, 32% (95% CI, 29% to 34%) for moderate, and 45% (95% CI, 42% to 48%) for severe ARDS ( P < 0.001).
The oxygen saturation by pulse oximetry (SpO 2 )/F io 2 correlates with Pa o 2 /F io 2 in patients with ARDS and was considered as an alternative for oxygenation criteria in the revised definition. Concerns regarding misclassification of ARDS severity when SpO 2 was 100% led its exclusion from the revised definition.
The inclusion of minimum PEEP levels in the Berlin definition was intended to address concerns regarding the influence of PEEP titration on Pa o 2 /F io 2 . Severity of oxygenation impairment, important for the diagnosis of ARDS and classification of disease severity, may fluctuate with PEEP and F io 2 titration. Moreover, PEEP-responsive patients appear to have a more favorable prognosis. The Berlin expert panel evaluated whether a higher PEEP threshold of 10 cm H 2 O or greater for severe ARDS improved prognostic performance with an individual patient-level meta-analysis. No change in prognostic performance was found; thus a PEEP threshold of 5 cm H 2 O was retained irrespective of ARDS severity in the final definition. However, PEEP titration was not standardized, and oxygenation responsiveness to PEEP titration was not assessed in the cohort used to examine the Berlin Pa o 2 /F io 2 thresholds. Both may have prognostic utility and are discussed in greater detail later in this chapter.
Chest Radiographic Findings
Interobserver agreement on radiographic interpretation with the AECC definition was remarkably poor. In a sample of 21 experts reviewing 28 randomly selected chest radiographs from patients with a Pa o 2 /F io 2 less than 300 mm Hg, the percentage of radiographs interpreted as consistent with ARDS ranged from 36% to 71%. Fewer than half of radiographs (43%) had near-complete agreement (agreement by 20 of 21 experts), and fully one third had at least five dissenting interpretations. A subsequent study evaluating whether consensus training improved interobserver agreement demonstrated improved agreement on radiographic diagnosis when two interpreters received training (88% to 94% of all pairwise interpretations). However, when one of the two interpreters did not receive training, interobserver agreement remained moderately poor (68% to 78% of all pairwise interpretations). To address this issue, the Berlin definition explicitly requires that opacities on chest imaging not be fully explained by effusions, lobar collapse, or nodules. In addition, the Berlin expert panel provided 12 sample radiographs with accompanying interpretations as consistent, inconsistent, or equivocal for diagnosis of ARDS.
The Berlin expert panel also considered quantifying radiographic opacities by number of involved quadrants. In a study of organ donors whose lungs were not used for transplantation, Ware and colleagues compared excised lung weight with a score quantifying the degree of pulmonary edema within each quadrant on frontal radiograph. They found good correlation between radiographic assessment and lung weight ( r = 0.61, P < 0.0001) that improved when radiographs with atelectasis were excluded ( r = 0.79, P < 0.0001). Likewise, detailed assessment of chest computed tomography found that increased lung attenuation and the proportion of nonaerated lung predict mortality in patients with ARDS. In an individual patient-level meta-analysis by the Berlin expert panel, prognostic performance of the severe ARDS classification was not improved with the additional requirement of three or more involved quadrants; thus the number of quadrants with radiographic infiltrates was not included in the final definition. Still, detailed radiographic interpretation better quantifying the extent of pulmonary edema may yield additional prognostic information if interobserver agreement can be improved.
Origin of Edema
The AECC definition required a PAWP of 18 mm Hg or less when measured or that there be no clinical evidence of left atrial hypertension. This aspect of the definition, as for definitions that preceded it, precluded the diagnosis of ARDS in patients with coincident ARDS and left atrial hypertension. Subsequent to the AECC definition, a multicenter study of 71 patients with ARDS and pulmonary artery catheters found that 82% of patients had at least one PAWP greater than 18 mm Hg when measured serially every 8 hours for the duration of catheter placement. In more than half of patients, PAWP exceeded 18 mm Hg on at least 30% of measurements. In the National Heart, Lung, and Blood Institute (NHLBI) ARDS Network Fluid and Catheter Treatment Trial, 29% of 513 enrolled ARDS patients randomized to receive a pulmonary artery catheter had an initial PAWP greater than 18 mm Hg, 97% of whom also had a normal or high cardiac index that made systolic heart failure an unlikely explanation for the high PAWP.
Recognizing that patients with heart failure are also vulnerable to lung injury and the development of ARDS, the Berlin definition explicitly allows for both hydrostatic and nonhydrostatic pulmonary edema to be present, requiring only that hydrostatic edema not be the primary cause of respiratory failure. Because pulmonary artery catheter use has substantially declined and judgment is necessary to determine the primary cause of respiratory failure, illustrative clinical vignettes were provided in the supplementary material for the Berlin definition. In addition, the Berlin definition stipulates that if no ARDS risk factor can be identified, objective assessment to exclude hydrostatic edema, such as by echocardiography, is required.
Ancillary Variables Considered
Static C RS and dead-space fraction were thought by the Berlin expert panel to have sufficient supporting data to warrant consideration in the definition. Decreased C RS has been recognized as a key feature since the original description of ARDS by Ashbaugh and colleagues. However, chest wall mechanics independent of lung injury often contribute substantially and unpredictably to global respiratory system mechanics, potentially limiting the prognostic utility of C RS in ARDS. In an individual patient-level meta-analysis, the Berlin expert panel found that including C RS of 40 mL/cm H 2 O or less in the diagnostic criteria for severe ARDS did not improve prognostic performance; thus it was excluded from the final definition.
Pulmonary dead-space fraction has been identified repeatedly as an independent predictor of mortality in epidemiologic studies of ARDS. However, dead-space fraction may fluctuate with changes in ventilator settings analogous to issues surrounding Pa o 2 /F io 2 . Because the dead-space fraction is not routinely measured in most ARDS clinical trials or in clinical practice, the Berlin expert panel considered corrected minute ventilation (minute ventilation × partial pressure of carbon dioxide in arterial blood [Pa co 2 ]/40) as a surrogate. Including corrected minute ventilation greater than 10 L/min as a criterion for severe ARDS did not improve prognostic performance in the Berlin individual patient-level meta-analysis ; thus it was also excluded from the final definition. However, corrected minute ventilation has not previously been validated as a surrogate for dead-space fraction. Other thresholds for C RS and corrected minute ventilation were not considered in formulating the Berlin definition.
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