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Acute respiratory distress syndrome (ARDS) is a major cause of acute hypoxemic respiratory failure in critically ill patients and is associated with substantial mortality. Current management is largely supportive, and no pharmacologic therapy has been shown consistently to reduce mortality in a broad population of patients with ARDS. Inflammation plays a central role in the pathogenesis of ARDS. Excessive inflammatory activation contributes to alveolar-capillary injury, impaired gas exchange, and progression of organ dysfunction. Glucocorticoids may mitigate these processes and have been associated in some studies with improved clinical outcomes, including shorter duration of mechanical ventilation. However, the effect of glucocorticoids on survival remains uncertain.
ARDS is a heterogeneous syndrome with diverse etiologies, and treatment response may vary according to the underlying cause. A post hoc analysis of the Dex-ARDS trial suggested that the treatment effect of glucocorticoids may be greater in ARDS caused by pneumonia or extrapulmonary sepsis. In a cross-sectional survey of 135 patients with ARDS from 20 ICUs in China, pneumonia- and extrapulmonary sepsis-associated ARDS accounted for 77.6% of cases, indicating that these are the predominant etiologic subtypes encountered in clinical practice in China. More importantly, compared with ARDS attributable to other causes, pneumonia- and extrapulmonary sepsis-associated ARDS has been associated with higher mortality, suggesting a greater disease burden, worse prognosis, and a more urgent need for improved treatment strategies. On this basis, the present trial will enroll patients with ARDS caused by sepsis, including pneumonia and extrapulmonary sepsis.
The primary hypothesis of this study is that, among patients with sepsis-associated ARDS, dexamethasone plus usual care, as compared with placebo plus usual care, will reduce 90-day all-cause mortality. We therefore designed a multicenter, randomized, double-blind, controlled trial to evaluate the clinical efficacy of dexamethasone in patients with sepsis-associated ARDS. The primary objective is to compare dexamethasone plus usual care with placebo plus usual care with respect to 90-day all-cause mortality.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dexamethasone Group | Experimental | Dexamethasone plus usual care |
|
| Placebo Group | Placebo Comparator | Placebo plus usual care |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexamethasone | Drug | Participants assigned to dexamethasone will receive 20 mg intravenously as soon as possible after randomization. Beginning after 10:00 am on the next calendar day following randomization, dexamethasone 20 mg will be administered once daily through day 5, followed by dexamethasone 10 mg once daily from Day 6 to Day 10. |
| Measure | Description | Time Frame |
|---|---|---|
| 90-day all-cause mortality | The proportion of participants who die from any cause between randomization (day 0) and day 90 (inclusive) | From randomization (day 0) to day 90 (inclusive) |
| Measure | Description | Time Frame |
|---|---|---|
| Ventilator-free days through day 28 | The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and successfully liberated from invasive mechanical ventilation | From randomization (day 0) to day 28 (inclusive) |
| Vasopressor-free days through day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of weaning success through day 28 | For intubated patients, successful weaning was defined as survival without reintubation within 7 days after extubation, or liberation from invasive mechanical ventilation with ICU discharge within 7 days. For tracheostomized patients, successful weaning was defined as spontaneous breathing via tracheostomy without mechanical ventilation for at least 7 consecutive days, or liberation from invasive mechanical ventilation with ICU discharge within 7 days. Reintubation for diagnostic purposes (e.g., bronchoscopy) or planned surgical procedures (e.g., wound debridement, abdominal lavage, internal fixation of fractures, tracheostomy) was not considered weaning failure. |
Inclusion Criteria:
(1) New or worsening respiratory symptoms or respiratory failure (2) Pulmonary infiltrates on chest radiography or computed tomography, or B-lines or consolidation on lung ultrasonography, not fully explained by pleural effusion, lobar or whole-lung collapse or atelectasis, or pulmonary nodules. Patients with unilateral pulmonary infiltrates, B-lines, or consolidation are eligible (3) Respiratory failure not fully explained by cardiac failure or fluid overload (4) Hypoxemia defined as PaO₂/FiO₂ of 300 mm Hg or less, or SpO₂/FiO₂ of 315 or less, with SpO₂ no greater than 97%.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Hui Chen, MD | Contact | +86-18006138640 | huichen.icu@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Jianfeng Xie, MD | Southeast University, Zhongda Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Zhongda Hospital, School of Medicine, Southeast University | Nanjing | Jiangsu | 210009 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | [1] MATTHAY M A, ARABI Y, ARROLIGA A C, et al. A New Global Definition of Acute Respiratory Distress Syndrome[J]. American Journal of Respiratory and Critical Care Medicine, 2024, 209(1): 37-47. [2] BELLANI G, LAFFEY J G, PHAM T, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries[J]. JAMA, 2016, 315(8): 788. [3] LIU L, YANG Y, GAO Z, et al. Practice of diagnosis and management of acute respiratory distress syndrome in mainland China: a cross-sectional study[J]. Journal of Thoracic Disease, 2018, 10(9): 5394-5404. [4] MATTHAY M A, ZEMANS R L, ZIMMERMAN G A, et al. Acute respiratory distress syndrome[J]. Nature Reviews Disease Primers, 2019, 5(1): 18. [5] MEDURI G U, GOLDEN E, FREIRE A X, et al. Methylprednisolone infusion in early severe ARDS[J]. Chest, 2007, 131(4): 954-963. [6] ANNANE D, SÉBILLE V, BELLISSANT E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome*:[J]. Critical Care Medicine, 2006, 34(1): 22-30. [7] TONGYOO S, PERMPIKUL C, MONGKOLPUN W, et al. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: Results of a randomized controlled trial[J]. Critical Care, 2016, 20(1): 329. [8] GRASSELLI G, CALFEE C S, CAMPOROTA L, et al. ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies[J]. Intensive Care Medicine, 2023, 49(7): 727-759. [9] VILLAR J, FERRANDO C, MARTÍNEZ D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial[J]. The Lancet Respiratory Medicine, 2020, 8(3): 267-276. [10] CHRIGUER R S, ROSELINO A M, DE CASTRO M. Glucocorticoid sensitivity and proinflammatory cytokines pattern in pemphigus[J]. Journal of Clinical Immunology, 2012, 32(4): 786-793. |
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Double blind, placebo controlled
|
|
| Placebo | Drug | Participants assigned to the placebo group will receive 0.9% sodium chloride injection as matching placebo, administered according to the same schedule as dexamethasone |
|
The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and successfully discontinued from vasopressor therapy |
| From randomization (day 0) to day 28 (inclusive) |
| Renal replacement therapy-free days through day 28 | The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and does not require renal replacement therapy | From randomization (day 0) to day 28 (inclusive) |
| 28-day all-cause mortality | The proportion of participants who die from any cause between randomization (day 0) and day 28 (inclusive) | From randomization (day 0) to day 28 (inclusive) |
| In-hospital mortality | The proportion of participants who die from any cause between randomization (day 0) and hospital discharge (inclusive). If a patient remains hospitalized for more than 90 days, 90-day mortality will be used as in-hospital mortality | Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days |
| 6-month all-cause mortality | The proportion of participants who die from any cause between randomization (day 0) and 6 months (inclusive) | From randomization (day 0) to 6 months (inclusive) |
| 12-month all-cause mortality | The proportion of participants who die from any cause between randomization (day 0) and 12 months | From randomization(day 0) to 12 months |
| Hospital-free days through day 90 | The number of days from randomization (day 0) to day 90 (inclusive) during which the patient is alive and does not require hospitalization | From randomization (day 0) to day 90 (inclusive) |
| Decision to withhold or withdraw active treatment during hospitalization | The proportion of participants in whom active treatment is withheld or withdrawn between randomization (day 0) and hospital discharge (inclusive) | Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days |
| Telephone Interview for Cognitive Status-Modified (TICS-m) | Cognitive status was assessed using a Chinese modified version of the Telephone Interview for Cognitive Status-modified (TICS-m). Higher scores indicate better cognitive performance | 90 days, 6 months and 12 months after randomization |
| Post-Traumatic Stress Disorder (PTSD) | Psychological outcomes will be assessed with the Post-traumatic Stress Disorder Checklist-Civilian Version (PCL-C, Chinese version). Respondents indicate how much they have been bothered by a symptom over the past month using a 5-point scale, with higher scores indicating more severe levels of PTSD. | 90 days, 6 months and 12 months after randomization |
| Health-related quality of life (EQ-5D-5L) | Health-related quality of life assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) instrument at 90 days, 6months and 12 months after randomization. The EQ-5D-5L measures health across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. | 90 days, 6 months and 12 months after randomization |
| Functional Activities Questionnaire (FAQ) | Caregiver-reported outcome, higher scores indicating worse impairment. | 90 days, 6 months, 12 months after randomization |
| Activities of daily living (ADL) score | Assessed using the Barthel Index, including feeding, bathing, grooming, dressing, bowel control, bladder control, toileting, chair/bed transfer, ambulation, and stair climbing, higher scores indicate greater independence. | 90 days, 6 months, 12 months after randomization |
| From randomization (day 0) to day 28 (inclusive) |
| Incidence of gastrointestinal bleeding through day 28 | The proportion of participants who developed acute gastrointestinal bleeding requiring transfusion of more than 1 unit of packed red blood cells within 24 hours | From randomization (day 0) to day 28 (inclusive) |
| Incidence of secondary bloodstream infection through day 28 | The proportion of participants who developed secondary bloodstream infection through day 28 | From randomization (day 0) to day 28 (inclusive) |
| Incidence of VAP through day 28 | The proportion of participants who developed ventilator-associated pneumonia through day 28 | From randomization (day 0) to day 28 (inclusive) |
| Incidence of hyperglycemia events through day 28 | The proportion of participants who had hyperglycemia events (blood glucose level >180 mg/dl) through day 28 | From randomization (day 0) to day 28 (inclusive) |
| ID | Term |
|---|---|
| D012128 | Respiratory Distress Syndrome |
| D018805 | Sepsis |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D003907 | Dexamethasone |
| C004180 | dexamethasone 21-phosphate |
| ID | Term |
|---|---|
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
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