Abstract
BackgroundAcute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies. Defining subphenotypes with distinct prognoses or biologic features can improve therapeutic trials, but prior work has focused on ARDS, which excludes many acute HRF patients. We aimed to characterize persistent and resolving subphenotypes in the broader HRF population.MethodsIn this secondary analysis of 2 independent prospective ICU cohorts, we included adults with acute HRF, defined by invasive mechanical ventilation and PaO2-to-FIO2 ratio ≤ 300 on cohort enrollment (n = 768 in the discovery cohort and n = 1715 in the validation cohort). We classified patients as persistent HRF if still requiring mechanical ventilation with PaO2-to-FIO2 ratio ≤ 300 on day 3 following ICU admission, or resolving HRF if otherwise. We estimated relative risk of 28-day hospital mortality associated with persistent HRF, compared to resolving HRF, using generalized linear models. We also estimated fold difference in circulating biomarkers of inflammation and endothelial activation on cohort enrollment among persistent HRF compared to resolving HRF. Finally, we stratified our analyses by ARDS to understand whether this was driving differences between persistent and resolving HRF.ResultsOver 50% developed persistent HRF in both the discovery (n = 386) and validation (n = 1032) cohorts. Persistent HRF was associated with higher risk of death relative to resolving HRF in both the discovery (1.68-fold, 95% CI 1.11, 2.54) and validation cohorts (1.93-fold, 95% CI 1.50, 2.47), after adjustment for age, sex, chronic respiratory illness, and acute illness severity on enrollment (APACHE-III in discovery, APACHE-II in validation). Patients with persistent HRF displayed higher biomarkers of inflammation (interleukin-6, interleukin-8) and endothelial dysfunction (angiopoietin-2) than resolving HRF after adjustment. Only half of persistent HRF patients had ARDS, yet exhibited higher mortality and biomarkers than resolving HRF regardless of whether they qualified for ARDS.ConclusionPatients with persistent HRF are common and have higher mortality and elevated circulating markers of lung injury compared to resolving HRF, and yet only a subset are captured by ARDS definitions. Persistent HRF may represent a clinically important, inclusive target for future therapeutic trials in HRF.
Highlights
Acute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies
Previous efforts to identify subphenotypes of respiratory failure have largely centered on acute respiratory distress syndrome (ARDS), which represents less than a quarter of patients on mechanical ventilation, and two-thirds of patients with acute HRF [9,10,11,12]
Patients with persistent HRF had higher illness severity and a higher proportion of ARDS on enrollment compared to patients with resolving HRF
Summary
Acute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies. Acute hypoxemic respiratory failure (HRF) is associated with extended hospital length of stay, functional disability, and increased mortality, but care remains supportive. One challenge in identifying effective therapeutics for a broadly defined syndrome like acute HRF is heterogeneity in treatment response and prognosis [6]. Defining reliable subsets of patients with high likelihood of disease-related events or differential treatment responses (often termed subphenotypes) can help target clinical care and trial enrollment to patients most likely to benefit [7, 8]. Previous efforts to identify subphenotypes of respiratory failure have largely centered on acute respiratory distress syndrome (ARDS), which represents less than a quarter of patients on mechanical ventilation, and two-thirds of patients with acute HRF [9,10,11,12].
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