EARLY-SARDS: Early AlveolaR Lung biologY Underling Sepsis-Associated ARDS (EARLY-SARDS)
Characterization of Early Biological and Mechanical Profiles in Sepsis-Associated ARDS for Studying Compartmentalization (Serial Bronchoalveolar Lavage and Plasma Biomarkers) to Identify Inflammatory and Hybrid Subphenotypes
Sepsis-associated acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure and mortality in critically ill patients. Although only a proportion of patients with sepsis develop ARDS, early identification of those at highest risk remains a major unmet clinical need. Current prediction relies largely on clinical deterioration and oxygenation impairment, which often occur when lung injury has already developed. Increasing evidence suggests that biological responses to sepsis are compartmentalized between the systemic circulation and the alveolar space, while early abnormalities in respiratory mechanics and ventilatory efficiency may provide complementary information on evolving lung injury. However, no prospective study has integrated serial systemic and alveolar biomarkers with bedside respiratory physiology during the earliest phase of sepsis-associated respiratory failure.
EARLY-SARDS is a prospective observational cohort study designed to characterize the early biological and physiological trajectories of invasively ventilated patients with sepsis or septic shock. Serial bronchoalveolar lavage (BAL) and plasma samples, together with standardized measurements of respiratory mechanics and gas exchange, will be collected during the first 96 hours after enrollment. The primary objective is to develop an integrated biological-physiological model capable of predicting ARDS development and subsequent peak ARDS severity. Secondary objectives include characterizing biological compartmentalization, identifying integrated biological-physiological subphenotypes, and evaluating their association with clinically relevant outcomes, including duration of mechanical ventilation, ventilator-free days, need for extracorporeal respiratory support, ICU length of stay, and mortality.
Study Overview
Status
Intervention / Treatment
Detailed Description
Acute respiratory distress syndrome (ARDS) secondary to sepsis is a biologically heterogeneous syndrome that reflects multiple interacting mechanisms of lung injury rather than a single pathological process. Current clinical definitions rely on physiological manifestations of established lung injury and therefore provide limited insight into the underlying biological processes responsible for disease initiation and progression.
Experimental and translational studies indicate that the earliest phase of sepsis-associated lung injury is characterized by dynamic interactions between inflammatory activation, epithelial injury, endothelial dysfunction, disruption of the alveolar-capillary barrier, and alterations in pulmonary permeability. These processes evolve rapidly during the first days after sepsis onset and may precede the clinical diagnosis of ARDS by several hours or days. Longitudinal characterization is therefore essential to understand the temporal evolution of lung injury.
Because the primary site of injury is the alveolar compartment, circulating biomarkers incompletely reflect the biological events occurring within the lung. Inflammatory mediators, epithelial injury markers, and endothelial activation frequently demonstrate compartmentalization between bronchoalveolar lavage (BAL) fluid and plasma, suggesting that simultaneous assessment of both compartments may provide a more comprehensive characterization of early lung injury than either compartment alone.
Respiratory physiology represents a complementary dimension of ARDS pathophysiology. Parameters including respiratory system compliance, driving pressure, plateau pressure, ventilatory ratio, and gas exchange describe the functional consequences of biological injury and the mechanical environment to which the lung is exposed during invasive mechanical ventilation. Mechanical stress and biological injury are closely interconnected and likely contribute jointly to disease progression.
By combining repeated assessment of alveolar biology, systemic host response, and respiratory physiology during the earliest phase of sepsis-associated respiratory failure, this study is designed to characterize the temporal evolution of lung injury and provide an integrated description of the biological and physiological mechanisms underlying progression to ARDS.
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Maria Martínez Pla, MD
- Phone Number: +34636602073
- Email: maria.martinezpla@vallhebron.cat
Study Contact Backup
- Name: Luis Morales Quinteros, MD, PhD
- Phone Number: +34 648493973
- Email: luisfernando.morales@vallhebron.cat
Study Locations
-
-
Barcelona
-
Barcelona, Barcelona, Spain, 08035
- Hospital Universitari Vall d'Hebron
-
Contact:
- Maria Martínez Pla, MD
- Phone Number: +34 636602073
- Email: maria.martinezpla@vallhebron.cat
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria
- Age ≥18 years.
- Sepsis or septic shock according to Sepsis-3 criteria.
- Requirement for invasive mechanical ventilation within 72 hours of sepsis diagnosis.
- Written informed consent provided by the participant or a legally authorized representative.
Exclusion Criteria
- Pregnancy.
- Previous lung transplantation.
- Contraindication to bronchoscopy or bronchoalveolar lavage (BAL).Inability to complete at least two BAL procedures during the 96-hour study period.
- Expected death within 24 hours or limitation of life-sustaining treatment at enrollment.
- Written informed consent not obtained.
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
|---|---|
|
Sepsis or Septic shock requiring mechanical ventilation
Adult ICU patients with sepsis or septic shock requiring invasive mechanical ventilation within 72 hours from sepsis diagnosis will be consecutively enrolled and followed for 96 hours after sepsis diagnosis.
|
At baseline (T0), blood samples and standardized respiratory physiological measurements, including gas exchange and ventilatory mechanics, will be obtained from all participants. Bronchoalveolar lavage (BAL) will be performed only in invasively mechanically ventilated patients meeting predefined safety criteria. T1 will occur 24 hours after T0 in patients already intubated or at the time of endotracheal intubation if this occurs within 72 hours of sepsis diagnosis. T2 will be performed 96 hours after sepsis diagnosis and at least 24 hours after the previous assessment. At each study point plasma sampling and physiological measurements will be repeated, while BAL will be repeated only when predefined safety criteria are fulfilled. All clinical management will remain at the discretion of the treating ICU team. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Early lung injury trajectory within 96 hours of sepsis onset
Time Frame: Baseline to 96 hours
|
Early lung injury trajectory, assessed as an ordinal composite endpoint integrating:
This endpoint will serve as the outcome for development and internal validation of an integrated biological-physiological prediction model combining alveolar and systemic biomarkers with respiratory physiological variables. |
Baseline to 96 hours
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Alveolar-systemic biological compartmentalization
Time Frame: Baseline to 96 hours
|
Alveolar-to-plasma biomarker gradients, concordance between paired bronchoalveolar lavage (BAL) and plasma biomarkers, and identification of compartmentalized biological profiles associated with early lung injury.
|
Baseline to 96 hours
|
|
Incremental predictive performance of integrated biological-physiological models
Time Frame: Baseline to 96 hours
|
Improvement in model discrimination, calibration, reclassification, and clinical utility after incorporation of alveolar biomarkers and respiratory physiological variables into conventional clinical and plasma-based prediction models.
|
Baseline to 96 hours
|
|
Reproducibility and external validation of biological-physiological models
Time Frame: Once study is completed, avarage 2 years
|
Assessment of biomarker distributions, alveolar-systemic gradients, biological-physiological subphenotype assignment, and prediction model performance across the prospective multicentre derivation cohort, including Vall d'Hebron and Uppsala University, with external validation in an independent retrospective Amsterdam UMC cohort.
|
Once study is completed, avarage 2 years
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Maria Martínez Pla, MD, SODIR (Shock, Disfunció Orgànica i Ressuscitació)
- Study Director: Luis Chiscano Camon, MD, PhD, SODIR (Shock, Disfunció Orgànica i Ressuscitació)
- Study Chair: Luis Morales Quinteros, MD, PhD, SODIR (Shock, Disfunció Orgànica i Ressuscitació)
- Study Director: Juan Carlos Ruiz Rodriguez, MD, PhD, SODIR (Shock, Disfunció Orgànica i Ressuscitació)
Publications and helpful links
General Publications
- Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA; NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014 Aug;2(8):611-20. doi: 10.1016/S2213-2600(14)70097-9. Epub 2014 May 19.
- Serpa Neto A, Deliberato RO, Johnson AEW, Bos LD, Amorim P, Pereira SM, Cazati DC, Cordioli RL, Correa TD, Pollard TJ, Schettino GPP, Timenetsky KT, Celi LA, Pelosi P, Gama de Abreu M, Schultz MJ; PROVE Network Investigators. Mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts. Intensive Care Med. 2018 Nov;44(11):1914-1922. doi: 10.1007/s00134-018-5375-6. Epub 2018 Oct 5.
- Zhang S, Duitman J, Artigas A, Bos LDJ. The Complex Immune Cell Composition and Cellular Interaction in the Alveolar Compartment of Patients with Acute Respiratory Distress Syndrome. Am J Respir Cell Mol Biol. 2025 Mar;72(3):233-243. doi: 10.1165/rcmb.2024-0176TR.
- Bos LD, Schouten LR, van Vught LA, Wiewel MA, Ong DSY, Cremer O, Artigas A, Martin-Loeches I, Hoogendijk AJ, van der Poll T, Horn J, Juffermans N, Calfee CS, Schultz MJ; MARS consortium. Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis. Thorax. 2017 Oct;72(10):876-883. doi: 10.1136/thoraxjnl-2016-209719. Epub 2017 Apr 27.
- Calfee CS, Janz DR, Bernard GR, May AK, Kangelaris KN, Matthay MA, Ware LB. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest. 2015 Jun;147(6):1539-1548. doi: 10.1378/chest.14-2454.
- Auriemma CL, Zhuo H, Delucchi K, Deiss T, Liu T, Jauregui A, Ke S, Vessel K, Lippi M, Seeley E, Kangelaris KN, Gomez A, Hendrickson C, Liu KD, Matthay MA, Ware LB, Calfee CS. Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis. Intensive Care Med. 2020 Jun;46(6):1222-1231. doi: 10.1007/s00134-020-06010-9. Epub 2020 Mar 23.
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- EARLY-SARDS-2025-11
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.