ABSTRACT
INTRODUCTION: SARS-CoV-2 has been associated with high rates of severe hypoxemic respiratory failure. Severe COVID-19 is characterized by rapid development of acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. ARDS is considered a heterogeneous disorder and the presence of a uniform inciting agent with SARS-CoV-2 allows us to investigate subphenotypes of ARDS. We hypothesized that subphenotypes based on early lung compliance in patients with COVID-ARDS may be associated with disease outcomes including mortality. We sought to test this hypothesis in patients with COVID-ARDS. METHODS: Patients in the Yale New Haven Health System from 3/15/2020 to 5/14/2020 were included if they had a positive SARS-CoV-2 test and required intubation. After exclusion for missing data or transfer from satellite facilities, 140 of patients were included for analysis. Clinical, demographic, ventilator, and laboratory parameters were abstracted from the EMR. To identify ARDS subphenotypes, we implemented unsupervised clustering using a partitioning around medoids (PAM) algorithm on average compliance over the three days following intubation. Clustering was also performed on the NHLBI ALVEOLI cohort for use as comparator. RESULTS: Patients received a median of 6.2 cc/kg of IBW on day 1 and 6.2 on day 3. Plateau pressure was less than 30cm H2O in 81% patients and driving pressure was less than 15 in 69% of patients. Median lung compliances were day 1: 30.4 mL/cm H2O [23.0-36.1];day 2: 28.7 mL/cm H2O [21.6-36.8];and day 3: 29.7 mL/cm H2O [23.2-37.6]. By Berlin criteria, 21% of patients had mild ARDS, 46% moderate, and 26% were severe. 61% of patients were proned. Using PAM, three distinct clusters based on compliance were identified (low [LC], medium [MC], and high [HC]). Median day 1 compliance in HC group was 38.0 mL/cm H2O [33.1-44.2], 29.3 [25.2-32.3] in MC, and 19.5 mL/cm H2O [16.7-22.8] in LC. Compared to the HC group, there were no differences in PEEP, day 1 P/F ratio or tidal volume, and ventilatory ratio. HC group had higher P/F ratio day 3, lower tidal volume day 3, and lower driving pressures. There were no differences in biomarkers, comorbidities, vasopressors, paralytics, or sedatives between groups. However, Kaplan-Meier plot demonstrated higher mortality in the HC group. Cox regression model demonstrated persistence of higher mortality in the HC compared to MC group. These differences were not present in the ALVEOLI cohort. CONCLUSION: In COVID-ARDS, a subphenotype characterized by early high compliance was associated with higher mortality when compared to non-COVIDARDS patients.