ARDS: progress unlikely with non-biological definition.

Accurate disease definitions are essential for clinical decisionmaking, trial enrolment, and mechanistic research. Since it was first recognized over four decades ago multiple attempts have been made to adequately define the acute respiratory distress syndrome (ARDS). However, up to half of the patients captured by definitions to date do not have the disease. This poor diagnostic accuracy may, in part, explain how over 200 randomized control trials have, with the exception of a low tidal volume ventilation strategy, failed to identify any mortality-reducing therapies. The recently published Berlin definition of ARDS was introduced to address the poor accuracy and shortcomings associated with previous models; however, a recent validation study found the diagnostic reliability of the Berlin definition to be no superior to its predecessor. In the absence of accurate, objectively validated criteria for diagnosing this condition, clinical trials will continue to include large numbers of patients without the disease. ARDS is a non-pneumonic, non-cardiogenic condition characterized by increased vascular permeability, pulmonary oedema, and severe arterial hypoxaemia—a clinical triad found in many critically ill patients. It is precipitated by both direct and indirect causes, resulting in a variable clinical pattern of presentation and progression. ARDS is frequently associated with other organ failures, resulting in both pulmonary and extra-pulmonary factors influencing mortality. Unlike most medical conditions, this complex syndrome does not yet benefit from an accessible in vivo reference standard (e.g. diagnosis of pulmonary embolism), or the existence of clear biomarkers (e.g. acute coronary syndrome). As a result, separating true ‘lung injury’ from other conditions, such as heart failure or pneumonia, which display similar clinical signs, is challenging. Although the reference standard has so far remained constant, lack of clarity about the clinical definition of ARDS has been problematic. Since 1967, when Ashbaugh and Petty first described the syndrome, there have been attempts to refine its definition. Initially, Murray proposed a definition comprising four variables—chest X-ray (CXR) findings, PaO2 /FIO2 ratio, positive end expiratory pressure (PEEP), and respiratory compliance. The resultant lung injuryscore (LIS) predicts the need for prolonged mechanical ventilation and has good sensitivity and specificity (0.74 and 0.77, respectively) as a predictor of diffuse alveolar damage (DAD) at autopsy. 4 Despite this, the LIS has not entered routine practice, and a more pragmatic approach that targets ease of use has prevailed. In 1994, the American-European Consensus Conference (AECC) redefined ARDS using criteria based on hypoxaemia, CXR infiltrates, and absence of left atrial hypertension; abnormal lung mechanics were dropped as a criterion. The AECC authors also urged diagnostic caution ‘in order to minimize the chance of including non-ARDS-related illnesses’. Their criteria are accessible, were adopted in widespread clinical practice, and were used as entry criteria in major clinical trials, without prior validation against pathological data. However, specificity is low (Table 1), and when lung biopsy is undertaken in seriously ill patients fulfilling the criteria, a diagnosis other than ARDS that necessitates a change in treatment is found in 60% of cases. If a sensitivity of 0.80 and specificity of 0.50—as reported by Ferguson and colleagues—are typical, then in critically ill patients with an ARDS prevalence of 30%, the AECC criteria have a positive predictive value (PPV) and negative predictive value (NPV) of 0.41 and 0.85, respectively. Although the definition may be useful in a screening role, 50% or more of patients diagnosed with ARDS by AECC criteria have another condition; AECC-based diagnosis exposes patients to the base rate fallacy, in which pretest probability and test likelihood ratios are unknown, the distinction between sensitivity and PPV is blurred, and diagnosis is based on pattern recognition. This may result in inability to translate basic science findings, underpowered trials, and misalignment of trial results with clinical practice. A new, improved definition of ARDS was required. The consensus-based Berlin definition proposed the subdivision of ARDS into three categories based on degree of hypoxaemia. Some AECC criteria—timing of insult, CXR pattern, and evaluation of patients with left atrial hypertension—were refined, and two new variables added—an explicit ‘risk factor’ requirement and PEEP of ≥5 cm H2O. Static compliance and expired minute ventilation were examined post hoc in a single subgroup, but not included in the final iteration, and the need to outrule ‘non-ARDS-related illnesses’ was not discussed. In the validation dataset, the new definition did not identify a BJA Editorial II