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.
BACKGROUND: Prior clinical trials established the safety, but not the efficacy of bone marrow-derived mesenchymal stromal cells (MSCs) in the acute respiratory distress syndrome (ARDS). METHODS: We conducted a prospective, double-blind, multi-center randomized phase 2b clinical trial of one dose of intravenous MSCs (10 x 10 FINDINGS: Enrollment began in January 2020. Due to the Coronavirus 2019 (COVID-19) pandemic, the majority of subjects (101/120, 84%) developed ARDS from COVID-19. There were no significant baseline differences in severity of illness between patients treated with MSCs and those who received placebo in the entire cohort of 120 patients or in the 101 patients with COVID-19 ARDS. There was no difference in the primary endpoint of change in oxygenation index from baseline over 36 hours after study product administration for the entire cohort or the COVID-19 subgroup, nor were there significant differences in mortality at 14, 28, 60 or 180 days. Plasma protein biomarker and gene expression analyses identified sub-groups of patients with differential treatment responses in terms of clinical outcomes. INTERPRETATION: This phase 2b clinical trial identified no physiologic or clinical benefit from a single dose of MSCs in patients with ARDS, including those with COVID-19 ARDS. In future trials, baseline plasma biological markers may help identify patients who are more likely to benefit from MSCs therapy. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03818854.
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.
BACKGROUND: Our study aimed to assess the effects of inhaled nitric oxide (iNO) on ventilation/perfusion mismatch, and individual variability in patients with acute respiratory distress syndrome (ARDS) by electrical impedance tomography (EIT). METHODS: This single-center, prospective physiological study enrolled mechanically ventilated ARDS patients. All patients initially received 5 ppm iNO; responders (≥ 20% increase in PaO RESULTS: At 30 min, 36.7% (11/30) of patients responded, associated with younger age and lower prevalence of hypertension. Among responders, the proportion of ventral perfusion significantly increased at 3 h, with this change already observed at 30 min. Responders also showed a significant reduction in the proportion of only perfused units in the dorsal region at 30 min; at the whole-lung level, the proportions of only perfused units and unmatched units decreased. In contrast, non-responders showed an increased proportion of only perfused units in both the dorsal region and whole lung at 3 h compared to baseline, following prolonged high-dose iNO administration. CONCLUSIONS: The response to iNO varied. In responders, EIT showed a potential redistribution of lung perfusion toward ventral regions, with reductions in the proportions of only perfused units and unmatched units in the whole lung.
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.
PURPOSE: COVID-19-associated pulmonary aspergillosis (CAPA) is a major co-infection in critically ill patients and is linked to increased mortality. Critical illness and ECMO may affect antifungal pharmacokinetics, raising concerns about drug efficacy. METHODS: This multicenter retrospective study included CAPA patients requiring mechanical ventilation in 20 intensive care units (ICUs) (March 2020 to November 2021), provided at least one antifungal blood level was available. The primary objective was to evaluate whether ECMO influenced the risk of subtherapeutic voriconazole levels. Secondary objectives included analyzing other antifungals and identifying risk factors for underdosing. RESULTS: Among 166 patients, 81 were on ECMO. A total of 358 voriconazole trough concentrations were collected in 150 patients. Subtherapeutic levels (<2 mg/L) were observed in 58 patients (39%) at first sampling and in 84 patients (56%) during the ICU stay, with no difference between ECMO and non-ECMO groups. No correlation was found between ECMO membrane duration and voriconazole levels. Daily dose was associated with low levels in univariate analysis only. Among 26 patients treated with isavuconazole, 11 (42%) had initial subtherapeutic levels. Renal replacement therapy, not ECMO, was associated with low isavuconazole levels (odds ratios = 7.5, P = 0.029). CONCLUSION: Over half of CAPA patients had subtherapeutic antifungal levels, but ECMO did not significantly influence drug exposure.