Acute Respiratory Distress Syndrome
Conditions
Keywords
Acute Respiratory Distress Syndrome, Acute Lung Injury, ARDS, ALI, aspirin, prevention
Brief summary
The primary hypothesis was that early aspirin administration will decrease the rate of developing acute lung injury during the first 7 days after presentation to the hospital.
Detailed description
Acute respiratory distress syndrome (ARDS) remains a life-threatening critical care syndrome characterized by alveolar-capillary membrane injury and hypoxemic respiratory failure. The median time to onset of ARDS is 2 days after hospital presentation. Therefore, the period between hospital presentation and the development of ARDS presents a brief window of opportunity for ARDS prevention. This was a multicenter, double-blind, placebo-controlled, parallel-group, Phase 2b, randomized clinical trial. Development of ARDS was defined by Berlin criteria (modified to require invasive mechanical ventilation) within 7 days of hospital admission. The first dose of study drug or placebo was administered within 24 hours after presentation to the hospital. Important co-interventions were standardized across sites using a web-based tool, Checklist for Lung Injury Prevention. Study participants were screened daily for receipt of mechanical ventilation and determination of the partial pressure of arterial oxygen (PaO2) or oxygen saturation to fraction of inspired oxygen ratio (SpO2:FIO2). If the participant's SpO2:FIO2 ratio was consistently below 315, hypoxemia was confirmed with measurement of arterial blood gas. Chest radiographs for all intubated patients with a SpO2:FIO2 of 300 or less were independently reviewed by both site investigator and a member of the trial's executive committee. Study participants who died or were discharged from the hospital before day 7 without meeting criteria for ARDS were adjudicated as not having ARDS.
Interventions
DRUGAspirin
325mg loading dose once on study day 1, followed by 81mg dose once daily on study days 2-7. Administered by mouth or down nasal gastric tube.
DRUGLactose powder
Matching lactose powder filled capsules will be administered on days 1-7.
Sponsors
Beth Israel Deaconess Medical Center
Montefiore Medical Center
Vanderbilt University Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients (age \> 18) admitted to the hospital through the emergency department (ED) * At high risk of developing acute lung injury (ALI) Lung Injury Prediction Score (LIPS) greater than or equal to 4
Exclusion criteria
* Anti-platelet therapy on admission or within 7 days prior to admission * Presented to outside hospital ED \> 12 hrs before arrival at site's facility * Inability to obtain consent within 12 hours of hospital presentation * Admitted for elective surgery * Acute lung injury prior to randomization * Receiving mechanical ventilation through a tracheostomy tube prior to current hospital admission (patient who is ventilator dependent) * Presence of bilateral pulmonary infiltrates on admission if he or she has a history of bilateral pulmonary infiltrates (as evidenced by previous x-rays) that can reasonably explain the current degree of pulmonary infiltrates present. * Presentation due to pure heart failure and no other known risk factors for ALI. * Allergy to aspirin or non steroidal anti inflammatory drugs (NSAIDs) * Bleeding disorder * Suspected active bleeding or judged to be at high risk for bleeding * Active peptic ulcer disease (within past 6 months) * Severe chronic liver disease * Inability to administer the study drug * Expected hospital stay \< 48 hours * Admitted for comfort or hospice care * Patient, surrogate or physician not committed to full support. (Exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest) * Not anticipated to survive \> 48 hours * Previously enrolled in this trial * Enrolled in a concomitant intervention trial * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Developed Acute Respiratory Distress Syndrome (ARDS) Within 7 Days | Within seven days from hospital presentation | ARDS was defined by Berlin criteria (modified to require invasive mechanical ventilation) within 7 days of hospital admission. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With ARDS or Mortality Within 7 Days | within 7 days |
| Number of Subjects With Mechanical Ventilation at Any Time During Hospitalization | approximately 7 days |
| Hospital Mortality | 28 days |
| Number of Subjects Admitted to Intensive Care Unit (ICU) | 7 days |
| Mean Hospital Length of Stay | approximately 7 days |
| Mean Number of Days Participants Were Ventilator-Free To Day 28 | baseline, Day 28 |
Countries
United States
Participant flow
Recruitment details
Participants were recruited between 1/2/2012 and 11/17/2014 at multiple US academic hospitals.
Participants by arm
| Arm | Count |
|---|---|
| Aspirin This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7. | 195 |
| Placebo This group received matching lactose powder filled capsules on days 1-7. | 195 |
| Total | 390 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent revoked | 5 | 1 |
| Overall Study | Inclusion criteria not met | 2 | 2 |
Baseline characteristics
| Characteristic | Aspirin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years | 57.0 years | 57 years |
| Region of Enrollment United States | 195 participants | 195 participants | 390 participants |
| Sex: Female, Male Female | 88 Participants | 99 Participants | 187 Participants |
| Sex: Female, Male Male | 107 Participants | 96 Participants | 203 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 195 | 5 / 195 |
| serious Total, serious adverse events | 4 / 195 | 8 / 195 |
Outcome results
Primary
Number of Participants Who Developed Acute Respiratory Distress Syndrome (ARDS) Within 7 Days
ARDS was defined by Berlin criteria (modified to require invasive mechanical ventilation) within 7 days of hospital admission.
Time frame: Within seven days from hospital presentation
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Number of Participants Who Developed Acute Respiratory Distress Syndrome (ARDS) Within 7 Days | 20 participants |
| Placebo | Number of Participants Who Developed Acute Respiratory Distress Syndrome (ARDS) Within 7 Days | 17 participants |
Comparison: The primary outcome significance level was adjusted for multiple testing associated with the interim analysis. Its significance level is 92.6%p-value: 0.53Wald
Secondary
Hospital Mortality
Time frame: 28 days
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Hospital Mortality | 14 participants |
| Placebo | Hospital Mortality | 14 participants |
p-value: >0.99Chi-squared
Secondary
Mean Hospital Length of Stay
Time frame: approximately 7 days
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Mean Hospital Length of Stay | 8.8 days | Standard Deviation 10.3 |
| Placebo | Mean Hospital Length of Stay | 9.0 days | Standard Deviation 9.9 |
p-value: 0.79Wilcoxon (Mann-Whitney)
Secondary
Mean Number of Days Participants Were Ventilator-Free To Day 28
Time frame: baseline, Day 28
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Mean Number of Days Participants Were Ventilator-Free To Day 28 | 24.9 days | Standard Deviation 7.4 |
| Placebo | Mean Number of Days Participants Were Ventilator-Free To Day 28 | 25.2 days | Standard Deviation 7 |
p-value: 0.72Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With ARDS or Mortality Within 7 Days
Time frame: within 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Number of Participants With ARDS or Mortality Within 7 Days | 27 participants |
| Placebo | Number of Participants With ARDS or Mortality Within 7 Days | 21 participants |
p-value: 0.36Chi-squared
Secondary
Number of Subjects Admitted to Intensive Care Unit (ICU)
Time frame: 7 days
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Number of Subjects Admitted to Intensive Care Unit (ICU) | 115 participants |
| Placebo | Number of Subjects Admitted to Intensive Care Unit (ICU) | 98 participants |
p-value: 0.08Chi-squared
Secondary
Number of Subjects With Mechanical Ventilation at Any Time During Hospitalization
Time frame: approximately 7 days
Population: Intention-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Number of Subjects With Mechanical Ventilation at Any Time During Hospitalization | 51 participants |
| Placebo | Number of Subjects With Mechanical Ventilation at Any Time During Hospitalization | 41 participants |
p-value: 0.23Chi-squared