Daily Ards Research Analysis
Analyzed 7 papers and selected 3 impactful papers.
Summary
Across multicenter ARDS ECMO cohorts, serum KL-6 measured around cannulation strongly associates with 90-day mortality and successful liberation, refining prognostication. Post-decannulation high fever shows opposite prognostic signals depending on concurrent infection status, emphasizing careful etiologic assessment. A breath-synchronized surfactant nebulization study demonstrates profound surfactant depletion in severe COVID-19 ARDS and rapid turnover of administered surfactant, informing dosing and delivery strategies.
Research Themes
- ECMO risk stratification using biomarkers
- Post-decannulation physiology and infection interplay
- Optimization of exogenous surfactant delivery and metabolism
Selected Articles
1. Association of Serum KL-6 With Mortality in Patients With Acute Respiratory Distress Syndrome (ARDS) Requiring Extracorporeal Membrane Oxygenation (ECMO): A Multicenter Retrospective Cohort Study.
In 373 severe ARDS patients on V-V ECMO across 24 hospitals, serum KL-6 measured within ±3 days of ECMO initiation was independently associated with higher 90-day mortality and, conversely, lower levels with successful ECMO liberation. The use of restricted cubic splines demonstrated a graded risk relationship, supporting KL-6 as a severity biomarker in the ECMO setting.
Impact: This multicenter cohort provides ECMO-specific validation of KL-6 as a prognostic biomarker, addressing a critical gap in risk stratification for the sickest ARDS patients.
Clinical Implications: KL-6 measurement around ECMO initiation could inform early prognostication, guide family counseling, and help stratify patients for trials or adjunctive therapies, potentially integrating into ICU risk models.
Key Findings
- Among 373 V-V ECMO patients, 90-day in-hospital mortality was 29.0% (108/373).
- Higher serum KL-6 near ECMO initiation was significantly associated with increased 90-day mortality (p=0.004) in multivariable Cox models with restricted cubic splines.
- Lower KL-6 levels were significantly associated with successful liberation from ECMO (p<0.001).
Methodological Strengths
- Multicenter cohort across 24 hospitals with a sizeable ECMO population (n=373).
- Robust multivariable Cox modeling using restricted cubic splines to capture nonlinearity.
Limitations
- Retrospective design with potential residual confounding and variability in KL-6 timing (±3 days).
- Single-timepoint biomarker measurement without external validation or defined clinical thresholds.
Future Directions: Prospective validation with serial KL-6 trajectories, threshold identification, integration with clinical scores, and evaluation of KL-6-guided management strategies.
Identifying reliable biomarkers associated with clinical outcomes in patients with acute respiratory distress syndrome (ARDS) receiving extracorporeal membrane oxygenation (ECMO) is essential. Elevated serum Krebs von den Lungen-6 (KL-6) has been linked to increased mortality in ARDS; however, its prognostic utility in ECMO remains unclear. This multicenter retrospective cohort study analyzed adult patients with severe ARDS who received veno-venous ECMO in 24 Japanese hospitals between 2012 and 2022. Serum KL-6 was measured within 3 days before or after ECMO initiation. The primary outcome was 90 day in-hospital mortality, and the secondary outcome was successful ECMO liberation. Among 373 patients, 265 (71.0%) survived, and 108 (29.0%) died. In multivariable Cox proportional hazards models using restricted cubic splines, higher KL-6 levels were significantly associated with increased 90 day mortality (p = 0.004), whereas lower KL-6 levels were significantly associated with successful liberation from ECMO (p < 0.001). These findings suggest that serum KL-6 measured around the time of ECMO initiation is associated with mortality and liberation outcomes in patients with, supporting its potential as a biomarker of disease severity.
2. Impact of post-decannulation high fever on mortality in patients with severe ARDS treated with veno-venous ECMO: a multicenter retrospective study.
Among 522 severe ARDS patients successfully weaned from V-V ECMO, 23.2% developed ≥39.0°C fever within 3 days post-decannulation. Overall mortality did not differ, but high fever predicted lower mortality when infection was present and higher mortality when infection was absent, highlighting a context-dependent prognostic signal.
Impact: This study clarifies that post-decannulation fever is not uniformly harmful or benign; its prognostic meaning flips with infection status, informing post-ECMO surveillance and management.
Clinical Implications: Evaluate for infectious complications at decannulation to contextualize fever; avoid reflexive suppression without diagnosis. Fever without infection may signal occult complications or dysregulated inflammation warranting closer monitoring and targeted workup.
Key Findings
- High fever (≥39.0°C within 3 days post-decannulation) occurred in 23.2% (121/522).
- Overall 90-day in-hospital mortality did not differ between fever and no-fever groups (19.0% vs 13.7%, p=0.372); multivariable HR 0.92 (95% CI 0.55–1.56).
- Infection present at decannulation: high fever associated with reduced mortality (HR 0.33, 95% CI 0.12–0.89, p=0.045); without infection: increased mortality (HR 2.25, 95% CI 1.23–4.11, p=0.011).
Methodological Strengths
- Large multicenter registry across 24 institutions with standardized fever definition.
- Cox proportional hazards modeling with prespecified subgroup analysis by infection status.
Limitations
- Post hoc analysis of a retrospective registry with potential residual confounding and infection misclassification.
- No standardized management of fever; causal mechanisms cannot be inferred.
Future Directions: Prospective studies to validate interaction with infection, incorporate biomarkers of host response, and test fever-guided post-ECMO care pathways.
BACKGROUND: Few studies have examined the prognostic impact of high fever after decannulation from veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome (ARDS). We aimed to investigate the incidence and prognostic significance of post-decannulation high fever in this population, exploring its association with mortality, stratified by the presence of infectious complications at decannulation. METHODS: This study was a post hoc analysis of a multicenter retrospective registry that included adult patients with severe ARDS who were successfully weaned off V-V ECMO between 2012 and 2022 across 24 institutions in Japan. High fever was defined as a core body temperature of ≥ 39.0 °C within 3 days after ECMO decannulation. The primary outcome was 90-day in-hospital mortality. Cox proportional hazards models were used to examine the association between post-decannulation high fever and mortality. As a subgroup analysis, we evaluated this association according to the presence or absence of infectious complications. RESULTS: Among 522 patients, 121 (23.2%) developed high fever within 3 days after ECMO decannulation. In the overall cohort, 90-day in-hospital mortality did not differ significantly between the high-fever and no-fever groups (19.0% vs. 13.7%, p = 0.372). Multivariable analysis showed no statistically significant association between high fever and mortality (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.55-1.56, p = 0.770). Subgroup analyses revealed opposite associations depending on infection status. High fever was associated with reduced mortality in patients with infection (HR 0.33, 95% CI 0.12-0.89, p = 0.045) but increased mortality in those without (HR 2.25, 95% CI 1.23-4.11, p = 0.011). CONCLUSIONS: Post-decannulation high fever occurs in nearly one-fourth of patients with severe ARDS treated with V-V ECMO. Its association with mortality appears to differ depending on the infection status at decannulation, underscoring the importance of carefully assessing infectious complications.
3. Surfactant nebulization in severe COVID-19: Tracheal aspirate phospholipid turnover and metabolism.
Using a breath-synchronized nebulizer, nebulized surfactant in severe COVID-19 ARDS achieved approximately 20-fold higher tracheal lipid levels over endogenous surfactant with a rapid median half-life of 7.8 hours. Lipidomic analyses revealed marked baseline surfactant depletion and indicated that exogenous dosing did not alter endogenous PC synthesis or composition.
Impact: This translational study couples a novel delivery platform with lipidomic mass spectrometry to quantify surfactant pharmacokinetics in vivo, addressing a key barrier to optimizing surfactant therapy in ARDS.
Clinical Implications: Findings support dose/delivery optimization of nebulized surfactant in ARDS, justify breath-synchronized nebulization, and inform trial design (dosing intervals, endpoints) though clinical benefit remains unproven.
Key Findings
- Tracheal aspirate at early intubation (n=20) showed markedly reduced surfactant phospholipids, indicating depletion.
- In 12 ventilated ARDS patients, nebulized surfactant achieved a mean 20-fold (range 6.4–60.3) excess over endogenous lipid in airway samples, confirming effective delivery.
- Administered surfactant exhibited rapid turnover with a median half-life of 7.8 hours (range 0.4–20.8 h).
- Endogenous tracheal PC synthesis rate and composition were not altered by exogenous surfactant dosing (per lipidomic tracing).
Methodological Strengths
- Breath-synchronized nebulizer enabling efficient surfactant delivery during mechanical ventilation.
- Lipidomic mass spectrometry with tracer incorporation to quantify phospholipid turnover and composition.
Limitations
- Small, nonrandomized dose-range case series with limited sample size.
- COVID-19-specific ARDS; no assessment of clinical outcomes (e.g., oxygenation, mortality).
Future Directions: Randomized trials to test clinical efficacy, dosing intervals informed by half-life, and exploration in non-COVID ARDS with standardized delivery protocols.
COV-SARS-2 targets alveolar type II cells. As these cells synthesise lung surfactant, we hypothesised that surfactant dysfunction may contribute to development of ARDS in COVID-19. Here we report turnover of surfactant delivered to patients ventilated for severe COVID-19 using a novel breath-synchronized nebulizer compared with a control group. Endogenous surfactant status, turnover and half-life of administered surfactant and tracheal aspirate (TA) phospholipid metabolism were analysed by lipidomic mass spectrometry. At enrolment shortly after intubation, TA analysis (n = 20) showed markedly reduced concentrations of surfactant phospholipids, consistent with surfactant depletion. In a dose-range study in 12 ventilated COVID-19 patients with ARDS, administered surfactant resulted mean 20-fold (range 6.4 and 60.3) excess over endogenous lipid, providing proof of concept for effective nebulization, with a very rapid turnover (median half-life 7.8, range 0.4 to 20.8 h). Neither the rate of endogenous TA phosphatidylcholine (PC) synthesis nor the composition of newly synthesised PC, determined by incorporation of methyl-D