Rapidly improving ARDS differs clinically and biologically from persistent ARDS

Background

Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes.

Methods

We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO₂:FiO₂ > 300 or (ii) SpO2: FiO₂ > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described.

Results

RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001).

Conclusions

This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.

Key Points

1. Prevalence and Clinical Course of RIARDS: RIARDS accounted for 21% of all ARDS cases in the cohort. These patients had significantly lower mortality (13% vs. 57%) and more ICU-free days (median 24 vs. 0) compared to persistent ARDS.
2. Defining RIARDS: RIARDS was identified based on either a PaO₂/FiO₂ > 300 or SpO₂/FiO₂ > 315 on day 2, or the ability to breathe unassisted by day 2 for at least 48 hours.
3. Inflammatory Biomarker Differences: RIARDS patients had significantly lower plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 (PAI-1), indicating a less pronounced inflammatory response compared to persistent ARDS.
4. Hypoinflammatory vs. Hyperinflammatory ARDS: The hypoinflammatory ARDS phenotype was significantly more common in RIARDS patients (78% vs. 51%), supporting the idea that lower systemic inflammation contributes to rapid improvement.
5. Ventilatory Differences: Persistent ARDS patients required higher positive end-expiratory pressure (PEEP), peak inspiratory pressure (PIP), and FiO₂, reflecting more severe lung injury and greater ventilatory support needs.
6. Differentiation from ARDS Mimics: Despite the rapid resolution of hypoxemia, biomarker analysis did not support the notion that RIARDS represents an ARDS mimic such as cardiogenic pulmonary edema. sRAGE levels, a marker of alveolar epithelial injury, were similar in both groups.
7. Clinical Implications for ARDS Management: The inclusion of RIARDS patients in clinical trials may obscure the effects of experimental therapies due to their rapid improvement. Identifying RIARDS early could allow for more personalized treatments.
8. Sensitivity Analyses in Severe ARDS: Even in patients who initially presented with severe ARDS (PaO₂/FiO₂ ≤ 100), those classified as RIARDS had lower inflammatory biomarker levels and better clinical outcomes.
9. Ethnicity and RIARDS Prevalence: RIARDS was more commonly observed in non-Hispanic patients, though the implications of this finding require further study.
10. Future Directions: Refining ARDS definitions to account for RIARDS, incorporating biomarkers into clinical decision-making, and leveraging predictive modeling could enhance personalized management strategies.

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