Evolving Epidemiology and Definitions of the Acute Respiratory Distress Syndrome and Early Acute Lung Injury

Andrew J. Sweatt, MD and Joseph E. Levitt, MD, MS*jlevitt@stanford.edu,     Division of Pulmonary and Critical Care Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA

*Corresponding author.

This article reviews the evolving definitions and epidemiology of the acute respiratory distress syndrome (ARDS) and highlights current efforts to improve identification of high-risk patients, thus to target prevention and early treatment before progression to ARDS. This information will be important for general practitioners and intensivists interested in improving the care of patients at risk for ARDS, and clinical researchers interested in designing clinical trials targeting the prevention and early treatment of acute lung injury.

Keywords

Acute respiratory distress syndrome

ARDS

Acute lung injury

ALI

Epidemiology

Prevention

Definition

Criteria

Key points

 Precise understanding of the epidemiology of the acute respiratory distress syndrome (ARDS) is limited by evolving clinical criteria and lack of an ideal reference standard.

 The recent Berlin Definition of ARDS addressed some limitations of prior definitions and empirically validated current criteria.

 As per the Berlin Definition, acute lung injury (ALI) is no longer a classification and ARDS severity is stratified as mild, moderate, and severe based on the Pao2/Fio2 ratio, and predicts mortality better than past definitions.

 The Lung Injury Prediction (LIPS) score and the Early Acute Lung Injury (EALI) score are novel criteria for identifying high-risk patients before progression to ARDS.

Introduction

Precise understanding of the epidemiology of the acute respiratory distress syndrome (ARDS) has been limited by evolution of the disease criteria over time and lack of an ideal reference standard. Defining ARDS by clinical and physiologic parameters provides feasibility in clinical practice, and has the advantage of conceptualizing the syndrome as a common final pathway of lung injury in response to a variety of inciting causes. However, eschewing pathologic correlation or other reference standards contributes to inclusion of heterogeneous patient populations with differing pathology and potentially very different prognoses. Also, defining a syndrome by criteria that are, in part, dependent on the institution of specific therapies may have significant implications for the epidemiology of the syndrome across countries and time periods because of differences in clinical practice patterns. This review discusses the evolving epidemiology and definition of ARDS, and recent efforts to improve recognition of patients at high risk of developing ARDS and enhance the prevention and early treatment of acute lung injury.

The evolution of acute respiratory distress syndrome and limitations of consensus criteria

ARDS was first described in a series of 12 patients in 1967 by Ashbaugh and colleagues,1 who recognized a common pattern of severe respiratory distress, refractory cyanosis, loss of lung compliance, and diffuse alveolar infiltrates in a variety of clinical contexts including sepsis, pneumonia, aspiration, and major trauma. Similar syndromes of acute respiratory failure had been previously recognized, but only as distinct conditions named for their specific inciting etiology (eg, Da Nang lung, shock lung, posttraumatic lung, respirator lung). A better understanding of risk factors for ARDS emerged in the early 1980s, but proposed definitions of the syndrome lacked uniformity.2,3

In 1994, the American and European Consensus Conference (AECC) established specific clinical criteria for ARDS and acute lung injury (ALI), a novel classification defined by similar criteria but requiring less severe oxygenation impairment.4 The AECC criteria defined ALI and ARDS as acute respiratory failure with bilateral pulmonary infiltrates on chest radiograph; a partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2) ratio less than 300 for ALI and less than 200 for ARDS; and absence of clinical evidence of left atrial hypertension or a pulmonary artery occlusion pressure less than 18 mm Hg. The AECC criteria were subsequently widely adopted, providing uniformity for epidemiologic studies, multicenter clinical trials, and clinical practice guidelines.

Despite offering feasibility and standardization, several limitations of the AECC criteria still exist. First, the meaning of respiratory failure was not clearly defined. Most multicenter clinical trials have limited enrollment to patients receiving mechanical ventilation via an endotracheal tube. However, in the most rigorous epidemiologic study to date, respiratory failure was interpreted to include mechanical ventilation via a noninvasive face mask or endotracheal tube.5 Other investigators have since expanded interpretation of the consensus criteria to include nonmechanically ventilated patients and those outside of the intensive care unit.6-9 Whether respiratory failure is interpreted as requiring intubation and/or some level of positive pressure ventilation or purely by Pao2/Fio2 ratio and radiographic criteria has major implications for anticipated incidence and outcomes. A pediatric study of patients in the emergency department with acute hypoxic respiratory failure, defined as a Pao2/Fio2 less than 300 (using a Pao2 derived from recorded saturations and charted Fio2), found that only 5% of patients subsequently required intubation.8 Another study of adults admitted to respiratory isolation rooms outside the intensive care unit demonstrated that patients with ALI (defined by bilateral infiltrates and hypoxemia) had similar mortality to those without one or both ALI criteria (12% vs 10%).9

In 2011, the ARDS Definition Task Force of the European Society of Intensive Care Medicine convened in Berlin to address limitations of the prior AECC definition and provide an empirical review of current and novel ancillary criteria.10,11 Factors limiting practicality and validity of the definition were identified as: lack of clear delineation of "acute"; confusion over inclusion of ARDS within the definition of ALI; failure to account for positive end-expiratory pressure (PEEP) in assessment of the Pao2/Fio2 ratio12-16; poor interobserver reliability in interpretation of bilateral infiltrates on chest radiograph17,18; inadequate sensitivity of high left atrial pressure for excluding cases of ARDS19,20; and absence of requirement of a known risk factor for ARDS. These issues may contribute to misidentification of ARDS, suboptimal stratification of severity of lung injury, and enrollment of a more heterogeneous population into clinical trials.

As proposed solutions, the Berlin Definition (Table 1) specifies that "acute" respiratory failure must occur within 1 week of predisposing illness, as supported by observational data revealing that nearly all patients develop ARDS within 7 days of an inciting insult.21 The prior ALI classification was eliminated, and instead ARDS is categorized by severity: mild (200 < Pao2/Fio2 =300), moderate (100 < Pao2/Fio2 =200), and severe (Pao2/Fio2 =100). This further stratification of severity below a Pao2/Fio2 ratio of 200 derives from prior evidence that mortality is highest in the lowest Pao2/Fio2 quartile independent of ventilator strategy,22,23 and prior trials indicating differential success of therapies according to the Pao2/Fio2 ratio.24-26 The Berlin Definition also requires a minimum PEEP of 5 cm H2O for all severity categories in recognition of the influence of PEEP on the Pao2/Fio2 ratio. The panel also clarified radiographic criteria with supporting teaching examples, and recognized the potential for ARDS and hydrostatic edema to coexist in the new definition. Because volume overload is common in patients with ARDS,20 criteria now exclude clinical evidence of isolated left atrial hypertension but without reference to a specific pulmonary artery occlusion pressure. Finally, the Berlin Definition specifies that use of noninvasive PEEP is allowed but limited to the mild ARDS category. This inclusion is in line with increasing use of noninvasive ventilation worldwide27 and will likely facilitate further study of noninvasive ventilation for mild ARDS, which continues to be a debated area of research.28-30

Table 1

The Berlin Definition of the...