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Critical Care Medicine www.ccmjournal.org 1955 Is an inferior wall myocardial infarction the same disease as an anterior wall myocardial infarction? Is breast cancer the same disease as ovarian cancer? These are fundamental questions whose answers require insights into the pathophysiology of the disease and the efficacy of different therapies. These are questions whose answers change over time, for example, as our understanding of cancer has advanced from morphologic sameness to cell replication mechanism sameness, some breast cancers are, in important ways, the same as some ovarian cancers (1). Acute respiratory distress syndrome (ARDS) is a common problem in critically ill patients, representing 10% of all ICU admissions and nearly 25% of patients requiring mechanical ventilation (2). Biologically, ARDS is characterized as acute lung inflammation, associated with increased pulmonary vascular permeability, increased lung weight, and acute loss of aerated lung tissue (3). Clinically, ARDS is, as it has been at least since 1967, a syndrome of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that cannot be attributed solely to heart failure and usually occurs in the setting of injury or infection (4). The question posed by García-de-Acilu et al (5) in this issue of Critical Care Medicine is “Is ARDS managed with highflow nasal cannula (HFNC) oxygen the same as ARDS managed with endotracheal ventilation?” This question has limited implications for clinicians as it does not address the question of the efficacy of HFNC in managing ARDS, and there are no unique pharmacologic therapies to offer patients on HFNC if we decide that they have ARDS. It is primarily of interest to researchers who may want support to enroll patients on HFNC in trials of therapy for ARDS and mechanistic studies of the syndrome. The question arises because patients on HFNC and other forms of supplemental oxygen are caught in a loophole in the most recent attempt to formalize the definition of ARDS which requires a Pao 2 /Fio 2 less than 300 on a positive end-expiratory pressure (PEEP) or continuous positive airway pressure of at least 5 cm water (4). Because of variability in measuring the Fio 2 and the delivered PEEP on HFNC (6), as well as the potential differences in the chest radiograph due to delivered tidal volume and respiratory rate, it is possible that some patients classified as having ARDS on HFNC might not meet these criteria if they had been intubated. Note, we specifically say “might not meet these criteria” instead of “might not have ARDS” as the developers of the Berlin Definition explicitly note that we do not have a laboratory test for “having ARDS” (4). One approach is to simply argue that the method by which a physician chooses to deliver oxygen cannot change the underlying mechanism of what she is treating. HFNC may select a group of patients with less severe ARDS if the delivered Fio 2 and PEEP are both lower than estimated, but there is no reason to suspect these patients have a different mechanism causing their acute hypoxemic respiratory failure assuming that they meet other diagnostic criteria. Those persuaded by this theoretical argument will find the article by García-de-Acilu M et al (5) superfluous and its findings intuitive. However, providing an empiric answer to the question of whether HFNC-ARDS is the same as intubated-ARDS is interesting, if for no other reason, because it requires us to address two fundamental issues: one biologic and the other statistical. In ARDS, the immune responses that lead to the structural and functional disruption of the alveolar endothelial and epithelial barrier are well described (3). Briefly, leukocytes sense presence of pathogens by detecting pathogen-associated molecular patterns such as lipopolysaccharide and tissue damage–associated molecular patterns such as mitochondrial nucleic acids with pattern recognition receptors, to generate a multitude of immune activation mediators through inflammasome and signalosome complexes (3, 7). Thus, the alveolar barrier disruption is the final common pathway resulting from a number of host responses that are not unique to ARDS, as similar host responses are seen in sepsis and trauma (3, 8, 9). Blood provides an accessible window to measure and evaluate biomarkers, which are indicators of normal biologic processes, pathogenic processes, or pharmacologic responses to therapeutic interventions. Recently, Terpstra et al (10) reported Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000002672 *See also p. 1845.