Daily Ards Research Analysis
A multicenter phase 2b RCT found no physiologic or survival benefit from a single intravenous dose of allogeneic mesenchymal stromal cells in ARDS, while exploratory biomarkers suggested potential responder subgroups. A prospective physiological study using electrical impedance tomography showed heterogeneous responses to inhaled nitric oxide with perfusion redistribution in responders. In CAPA, over half of patients had subtherapeutic azole concentrations, unaffected by ECMO but associated with
Summary
A multicenter phase 2b RCT found no physiologic or survival benefit from a single intravenous dose of allogeneic mesenchymal stromal cells in ARDS, while exploratory biomarkers suggested potential responder subgroups. A prospective physiological study using electrical impedance tomography showed heterogeneous responses to inhaled nitric oxide with perfusion redistribution in responders. In CAPA, over half of patients had subtherapeutic azole concentrations, unaffected by ECMO but associated with renal replacement therapy, reinforcing therapeutic drug monitoring.
Research Themes
- Precision phenotyping and enrichment strategies in ARDS
- Physiological monitoring to guide vasodilator therapy
- Therapeutic drug monitoring and pharmacokinetics in critical illness
Selected Articles
1. Treatment with Allogenic Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome: A Double-Blind, Placebo-controlled, Multi-Center, Phase 2b Clinical Trial (STAT).
In this multicenter, double-blind phase 2b RCT (n=120; 84% COVID-19 ARDS), a single intravenous dose of allogeneic MSCs did not improve the 36-hour oxygenation index or mortality at 14, 28, 60, or 180 days versus placebo. Exploratory plasma proteomics and transcriptomics suggested biologically defined subgroups with differential responses, supporting future biomarker-enriched trials.
Impact: A rigorously conducted RCT delivers a definitive negative efficacy signal for single-dose MSCs in ARDS and advances precision-medicine concepts via biomarker-defined subgroups.
Clinical Implications: Single-dose IV MSCs should not be used for ARDS outside trials. Future studies should consider biomarker-enriched populations, dosing strategies (repeat/earlier dosing), and robust phenotyping.
Key Findings
- No improvement in the primary endpoint (36-hour oxygenation index change) with MSCs versus placebo.
- No differences in mortality at 14, 28, 60, or 180 days.
- 84% of enrolled patients had COVID-19-related ARDS; baseline severity balanced between groups.
- Plasma protein and gene-expression analyses identified subgroups with differential clinical responses.
Methodological Strengths
- Prospective, double-blind, multicenter randomized controlled design with trial registration (NCT03818854).
- Predefined physiologic and clinical endpoints with exploratory multi-omic biomarker analyses.
Limitations
- Single-dose regimen; dosing frequency/timing not tested.
- Predominance of COVID-19 ARDS may limit generalizability to non-COVID ARDS.
- Biomarker subgroup findings are exploratory and require validation.
Future Directions: Biomarker-enriched RCTs evaluating alternative MSC dosing (repeat or earlier administration), cell sources, and combinations, with harmonized phenotyping and patient selection.
2. Effects of inhaled nitric oxide on ventilation/perfusion mismatch assessed by electrical impedance tomography in patients with ARDS: a prospective observational study.
In 30 mechanically ventilated ARDS patients receiving iNO, 36.7% met responder criteria (≥20% PaO2/FiO2 increase). EIT revealed that responders had a redistribution of perfusion toward ventral regions and reductions in only-perfused and unmatched units, whereas non-responders showed worsening perfusion-only units after prolonged high-dose iNO.
Impact: Provides mechanistic, bedside evidence using EIT to phenotype iNO responsiveness and V/Q effects, supporting personalized vasodilator use in ARDS.
Clinical Implications: EIT may guide selection and titration of iNO by identifying responders and avoiding potential harm in non-responders; supports short early assessments rather than prolonged empiric high-dose iNO.
Key Findings
- 36.7% (11/30) of ARDS patients were iNO responders at 30 minutes.
- Responders exhibited increased ventral perfusion and decreased only-perfused and unmatched units on EIT.
- Non-responders showed increased only-perfused units after prolonged high-dose iNO.
- Responders were younger and had lower prevalence of hypertension.
Methodological Strengths
- Prospective physiological design with prespecified responder definition (≥20% PaO2/FiO2 increase).
- Use of EIT to provide regional, real-time V/Q assessment at 30 minutes and 3 hours.
Limitations
- Single-center, small sample size limits generalizability.
- Physiologic endpoints without clinical outcome assessment; non-randomized and variable iNO dosing over time.
Future Directions: EIT-guided randomized trials to test iNO in identified responders, optimal dosing strategies, and linkage to clinical outcomes.
3. Antifungal concentrations in mechanically ventilated COVID-19 patients with or without ECMO: The CAPADOSE observational retrospective multicenter Study.
In 166 mechanically ventilated CAPA patients across 20 ICUs, subtherapeutic azole levels were common: 39% at first voriconazole sampling and 56% during ICU stay, with no differences between ECMO and non-ECMO. Isavuconazole underexposure occurred in 42% initially and was associated with renal replacement therapy, not ECMO.
Impact: Clarifies that ECMO does not systematically reduce azole exposure in CAPA, while highlighting the high prevalence of subtherapeutic levels and the influence of renal replacement therapy, directly informing TDM and dosing.
Clinical Implications: Routine therapeutic drug monitoring of azoles is warranted in CAPA regardless of ECMO status; particular vigilance is needed with renal replacement therapy to avoid underdosing.
Key Findings
- Subtherapeutic voriconazole levels occurred in 39% at first sampling and 56% during ICU stay.
- No differences in voriconazole exposure between ECMO and non-ECMO, and no correlation with ECMO membrane duration.
- Initial subtherapeutic isavuconazole in 42% of patients; renal replacement therapy associated with low isavuconazole levels (OR 7.5, P=0.029).
Methodological Strengths
- Multicenter ICU cohort with therapeutic drug monitoring across two azoles.
- Focused analysis of ECMO as a potential PK modifier with additional evaluation of RRT.
Limitations
- Retrospective design with potential confounding and non-standardized dosing strategies.
- Drug levels not systematically linked to clinical outcomes or microbiologic clearance.
Future Directions: Prospective studies to define azole dosing algorithms incorporating TDM, the impact of RRT modalities, and associations with clinical outcomes in CAPA/ARDS populations.