Respiratory Distress Syndrome, Adult
Conditions
Keywords
Acute Lung Injury, Acute Respiratory Distress Syndrome, Albuterol, Aerosolized, Critical Care, Ventilator
Brief summary
Acute Respiratory Distress Syndrome (ARDS) and a lesser condition that occurs prior to ARDS, Acute Lung Injury (ALI), are medical conditions that occur when there is severe inflammation and increased fluids (edema) in both lungs, making it hard for the lungs to function properly. Patients with these conditions require treatment that includes the use of a breathing machine (ventilator). The purpose of this study is to find out whether giving albuterol (a drug commonly used in asthmatics) or not giving albuterol to patients with ALI or ARDS makes a difference in how long it takes for a patient to be able to breath without the ventilator.
Detailed description
Aerosolized beta-2 agonist therapy is anticipated to diminish the formation of lung edema, enhance clearance of lung edema and decrease pulmonary inflammation in patients with acute lung injury. Because beta-2 agonists have been shown to reduce permeability induced lung injury, it is anticipated that the severity of lung injury will be reduced by aerosolized beta-2 agonist therapy. The therapy may work by enhancing resolution of pulmonary edema by upregulating alveolar epithelial fluid transport mechanisms that will in turn enhance the clearance of alveolar edema. A reduction in the severity of lung injury and the quantity of alveolar edema should result in earlier extubation and more ventilator free days, improved pulmonary oxygen uptake, and improved lung compliance. Study design: phase II/III prospective, randomized double-blind, placebo controlled trial. * In Phase II, patients will be treated with aerosolized albuterol 5.0 mg vs. normal saline (n=40-50)administered every 4 hours for 10 days following randomization or until 24 hours following extubation, whichever occurs first. The protocol stipulates that the 5.0 mg dose will be reduced to 2.5 mg if patients exceed defined heart rate limits. * In Phase III, the 5.0 mg dose will be used unless there is evidence that this dose has an unacceptable safety profile or dose reductions for tachycardia occur in a large fraction of patients. In that case, a lower dose of 2.5 mg will be used. * Patients will be followed for 90 days or until discharge from the hospital to home with unassisted breathing whichever occurs first.
Interventions
Albuterol sulfate, USP, solution for inhalation will be diluted as follows: * The full dose of 5.0 mg will be diluted into 2.0 ml of sterile normal saline solution. * The reduced dose of 2.5 mg will be diluted into 2.5 ml of sterile normal saline solution. A high-efficiency small volume jet nebulizer (SVN) powered at a flow of 8 liters/minute from a 50 psi wall oxygen flow meter will be used for continuous nebulization. The study drug will be given every 4 hours (plus or minus one hour) for ten days following randomization or until 24 hours after extubation, whichever occurs first.
PROCEDUREMini-Bronchoalveolar Lavage (BAL)
The mini-BAL procedure involves blind specimen sampling from distal airspaces. Specimens are obtained with the Combicath (Plastimed) catheter. The procedure will be done on study days 0 and 3
DRUGPlacebo
Placebo aerosol will consist of 3.0 ml of identical appearing sterile 0.9 % sodium chloride without preservative. A high-efficiency small volume jet nebulizer (SVN) powered at a flow of 8 liters/minute from a 50 psi wall oxygen flow meter will be used for continuous nebulization (e.g.: throughout the inspiratory and expiratory cycle). The study drug will be given every 4 hours (plus or minus one hour) for ten days following randomization or until 24 hours after extubation, whichever occurs first.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must meet the following three criteria within a 24-hour period: 1. Acute onset of PaO2/FiO2 less than or equal to 300 (adjustments made for altitude where appropriate) 2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph 3. Requirement for positive pressure ventilation via endotracheal tube * No clinical evidence of left-sided cardiac failure to account for bilateral pulmonary infiltrates
Exclusion criteria
* Greater than 48 hours since all inclusion criteria are met * Neuromuscular disease that impairs ability to ventilate without assistance, (e.g., cervical spinal cord injury at level C5 or higher spinal cord injury amyotrophic lateral sclerosis, Guillain-Barré syndrome or myasthenia gravis) * Pregnant or breast-feeding * Severe chronic respiratory disease (i.e., chronic hypercapnia \[PaCO2 greater than 45 mmHg\], chronic hypoxemia \[PaO2 less than 55 mmHg on FiO2 = 0.21\], hospitalization within the last 6 months for respiratory failure \[PaCO2 greater than 50 mm Hg and/or PaO2 less than 55 mmHg on 0.21 FiO2\], secondary polycythemia, severe pulmonary hypertension \[mean PAP (pulmonary artery pressure) greater than 40 mmHg\], or ventilator dependency) * Burns over greater than 40% of total body surface area * Cancer or other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50% * Allogeneic bone marrow transplant within the 5 years prior to study entry * Participant, surrogate, or physician is not committed to full support (Exception: a participant will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest) * Severe chronic liver disease (Child-Pugh score of 11-15) * Diffuse alveolar hemorrhage from vasculitis * Morbid obesity (greater than 1kg/cm body weight.) * Unwillingness or inability to utilize the ARDS network 6 ml / kg Predicted Body Weight (PBW) ventilation protocol * Moribund participant and is not expected to survive 24 hours * No intent to obtain central venous access for monitoring intravascular pressures * Contraindication to aerosolized albuterol (see Appendix A.8 of the protocol for more information) * Daily use (prior to study hospitalization) of inhaled beta agonist, corticosteroid, or oral leukotriene modifier * Unwillingness of primary physician to discontinue inpatient beta agonist use * Acute myocardial infarction or acute coronary syndrome within 30 days of study entry * Severe congestive heart failure (see Appendix A5 of the protocol for more information) * Participation in other experimental medication trial within 30 days of study entry with the exception of the ARDSNet pharmaconutrient nutrition trial (OMEGA) * Heart rate greater than 85% of maximal predicted heart rate (MHR85) as calculated by MHR85 = 85% x (220-age) * Currently receiving high frequency ventilation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Ventilator Free Days (VFD) | Determined 28 days after a subject entered the study | Ventilator-free days (VFDs) is defined as the number of days from randomization to Day 28 after achieving unassisted breathing for patients who maintained unassisted breathing for at least two consecutive calendar days. If a patient achieved unassisted breathing, subsequently required additional assisted breathing, and once again achieved unassisted breathing, we counted only the VFDs after beginning the final period of unassisted breathing. Patients who died before Day 28 were assigned zero VFDs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90 | Determined 90 days after a subject entered the study | Success for this efficacy variable was defined as being alive on study day 90 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those participants who still remained in the hospital at 90 days after randomization were considered to have survived. |
| Number of ICU-free Days at 28 Days After Randomization | Determined 28 days after a subject entered the study | ICU (intensive care unit)-free days was defined as the number of days a subject was out of the ICU during study hospitalization from date of randomization up to study day 28. All incidences of ICU admission and discharge during the study hospitalization were captured. Any portion of a calendar day that a subject was in the ICU was counted as an ICU day. |
| Number of Organ Failure-free Days at Day 28 Following Randomization | Daily from baseline to study day 28 | Subjects were followed for development of organ failures from date of randomization to hospital discharge or study day 28, whichever was first. Organ failure was defined as present on any calendar day when the most abnormal vital signs or clinically available lab value met the definition of clinically significant organ failure according to the Brussels Organ Failure Table. Each day a patient was alive and free of a given clinically significant organ failure was scored as a failure-free day. The worst value for a calendar day was captured (lowest systolic BP, platelet count and highest creatinine and bilirubin values). Specific definitions of organ failure were: cardiovascular-systolic BP less than or equal to 90 mmHg or on a vasopressor; coagulation-platelet count less than or equal to 80 x 1000/mm3; Renal-creatinine less than or equal to 2.0 mg/dL; Hepatic-bilirubin less than or equal to 2.0 mg/dL. |
| Ventilator Free Days to Day 28 in the Subset of Participants With ARDS | Determined 28 days after a subject entered the study | Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200). P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2. VFD to Day 28 is defined as the number of days from the end of ventilation to day 28 in patients who maintained unassisted breathing for at least two consecutive calendar days. Patients who died before day 28 were assigned a VFD count of zero. If a patient returned to assisted breathing, subsequently required assisted breathing, and once again achieved unassisted breathing, only the VFDs after beginning the final period of unassisted breathing were counted. An increase in the number of VFDs was considered a positive result. |
| Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60 | Determined 60 days after a subject entered the study | Success for this efficacy variable was defined as being alive on study day 60 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those subjects alive in hospital at day 60 were considered to have survived. |
| Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock | Determined 28 days after a subject entered the study | Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure\<60 or the need for vasopressors (except dopamine \<6 ug/kg/min). |
| Hospital Mortality up to Day 60 in Subjects With Baseline Shock | Determined 60 days after a subject entered the study | Difference in the main outcome hospital mortality to study day 60 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure\<60 or the need for vasopressors (except dopamine \<6 ug/kg/min). |
| Plasma Levels of IL-6 and IL-8 on Study Day 3 | Measured at baseline and 3 days after randomization | Biologic end-points were selected that would provide mechanistic insight into how albuterol improved lung function. Concentrations of two proinflammatory cytokines, interleukin 6 and 8 (IL-6 and IL-8), were measured. Plasma was collected and cytokine levels were measured at baseline and 3 days after randomization. IL-6 and IL-8 levels were normalized using log transformation. Wilcoxon's test was used to compare mean log-transformed interleukin levels per day and a mixed-effects model was fit to compare the slopes. |
| Hospital Mortality to Day 60 in the Subset of Participants With ARDS | Determined 60 days after a subject entered the study | Difference in the main outcome mortality to study day 60 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200) prior to randomization. P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2. |
Countries
United States
Participant flow
Recruitment details
The trial was conducted with a combined Phase II/III design to enroll 1000 patients with a safety review performed after 100 subjects were enrolled and interim analysis looks at 250, 500, and 700 subjects. The first subject was entered in August 2007 and the last subject in July of 2008 when the study was stopped for futility at 282 enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Albuterol Sulfate Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours | 152 |
| Placebo Preservative-free 0.9% sterile sodium chloride every 4 hours | 130 |
| Total | 282 |
Baseline characteristics
| Characteristic | Placebo | Albuterol Sulfate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical >=65 years | 27 Participants | 39 Participants | 66 Participants |
| Age, Categorical Between 18 and 65 years | 100 Participants | 111 Participants | 211 Participants |
| Age, Continuous | 50.9 years STANDARD_DEVIATION 16.2 | 52.3 years STANDARD_DEVIATION 16.4 | 51.6 years STANDARD_DEVIATION 16.2 |
| Gender Female | 59 Participants | 67 Participants | 126 Participants |
| Gender Male | 71 Participants | 85 Participants | 156 Participants |
| Region of Enrollment United States | 130 participants | 152 participants | 282 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 152 | 15 / 130 |
| serious Total, serious adverse events | 1 / 152 | 1 / 130 |
Outcome results
Primary
Number of Ventilator Free Days (VFD)
Ventilator-free days (VFDs) is defined as the number of days from randomization to Day 28 after achieving unassisted breathing for patients who maintained unassisted breathing for at least two consecutive calendar days. If a patient achieved unassisted breathing, subsequently required additional assisted breathing, and once again achieved unassisted breathing, we counted only the VFDs after beginning the final period of unassisted breathing. Patients who died before Day 28 were assigned zero VFDs.
Time frame: Determined 28 days after a subject entered the study
Population: All the intent to treat patients were analyzed. Data was available on all subjects for the primary analysis only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol | Number of Ventilator Free Days (VFD) | 14.4 days | Standard Error 0.9 |
| Placebo | Number of Ventilator Free Days (VFD) | 16.6 days | Standard Error 0.9 |
Comparison: The trial had a statistical power of 90.7% to detect a 2.25-day increase in VFDs,assuming a SD of 10.5 days. A group sequential design was used.p-value: 0.08795% CI: [-4.7, 0.3]ANCOVA
Secondary
Hospital Mortality to Day 60 in the Subset of Participants With ARDS
Difference in the main outcome mortality to study day 60 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200) prior to randomization. P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2.
Time frame: Determined 60 days after a subject entered the study
Population: Patients meeting the criteria for ARDS (pre-randomization PaO2/FiO2 ratio less than or equal to 200) were selected for this subset.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albuterol | Hospital Mortality to Day 60 in the Subset of Participants With ARDS | 24.5 percentage of participants who died |
| Placebo | Hospital Mortality to Day 60 in the Subset of Participants With ARDS | 16.3 percentage of participants who died |
p-value: 0.17695% CI: [-3.1, 19.6]Regression, Logistic
Secondary
Hospital Mortality up to Day 60 in Subjects With Baseline Shock
Difference in the main outcome hospital mortality to study day 60 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure\<60 or the need for vasopressors (except dopamine \<6 ug/kg/min).
Time frame: Determined 60 days after a subject entered the study
Population: Patients with protocol defined shock (mean arterial pressure\<60 or need for vasopressors except dopamine \< 6ug/kg/min) at the time of study entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albuterol | Hospital Mortality up to Day 60 in Subjects With Baseline Shock | 36.8 percentage of participants who died |
| Placebo | Hospital Mortality up to Day 60 in Subjects With Baseline Shock | 27.3 percentage of participants who died |
p-value: 0.26595% CI: [-6.9, 25.9]Regression, Logistic
Secondary
Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60
Success for this efficacy variable was defined as being alive on study day 60 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those subjects alive in hospital at day 60 were considered to have survived.
Time frame: Determined 60 days after a subject entered the study
Population: Intent to treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albuterol | Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60 | 23.0 percentage of participants who died |
| Placebo | Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60 | 17.7 percentage of participants who died |
p-value: 0.30295% CI: [-4, 14.7]Regression, Logistic
Secondary
Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90
Success for this efficacy variable was defined as being alive on study day 90 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those participants who still remained in the hospital at 90 days after randomization were considered to have survived.
Time frame: Determined 90 days after a subject entered the study
Population: Intent to treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albuterol | Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90 | 24.3 percentage of participants who died |
| Placebo | Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90 | 18.5 percentage of participants who died |
p-value: 0.26195% CI: [-3.7, 15.4]Regression, Logistic
Secondary
Number of ICU-free Days at 28 Days After Randomization
ICU (intensive care unit)-free days was defined as the number of days a subject was out of the ICU during study hospitalization from date of randomization up to study day 28. All incidences of ICU admission and discharge during the study hospitalization were captured. Any portion of a calendar day that a subject was in the ICU was counted as an ICU day.
Time frame: Determined 28 days after a subject entered the study
Population: Intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol | Number of ICU-free Days at 28 Days After Randomization | 13.5 days | Standard Error 0.8 |
| Placebo | Number of ICU-free Days at 28 Days After Randomization | 16.2 days | Standard Error 0.8 |
p-value: 0.02395% CI: [-4.9, -0.4]ANCOVA
Secondary
Number of Organ Failure-free Days at Day 28 Following Randomization
Subjects were followed for development of organ failures from date of randomization to hospital discharge or study day 28, whichever was first. Organ failure was defined as present on any calendar day when the most abnormal vital signs or clinically available lab value met the definition of clinically significant organ failure according to the Brussels Organ Failure Table. Each day a patient was alive and free of a given clinically significant organ failure was scored as a failure-free day. The worst value for a calendar day was captured (lowest systolic BP, platelet count and highest creatinine and bilirubin values). Specific definitions of organ failure were: cardiovascular-systolic BP less than or equal to 90 mmHg or on a vasopressor; coagulation-platelet count less than or equal to 80 x 1000/mm3; Renal-creatinine less than or equal to 2.0 mg/dL; Hepatic-bilirubin less than or equal to 2.0 mg/dL.
Time frame: Daily from baseline to study day 28
Population: Intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol | Number of Organ Failure-free Days at Day 28 Following Randomization | 14.2 days | Standard Error 0.9 |
| Placebo | Number of Organ Failure-free Days at Day 28 Following Randomization | 15.9 days | Standard Error 1 |
p-value: 0.22695% CI: [-4.3, 0.9]ANCOVA
Secondary
Plasma Levels of IL-6 and IL-8 on Study Day 3
Biologic end-points were selected that would provide mechanistic insight into how albuterol improved lung function. Concentrations of two proinflammatory cytokines, interleukin 6 and 8 (IL-6 and IL-8), were measured. Plasma was collected and cytokine levels were measured at baseline and 3 days after randomization. IL-6 and IL-8 levels were normalized using log transformation. Wilcoxon's test was used to compare mean log-transformed interleukin levels per day and a mixed-effects model was fit to compare the slopes.
Time frame: Measured at baseline and 3 days after randomization
Population: Not all subjects had available data for secondary analyses and therefor the numbers will be less than the 152 (active) and 130 (placebo) arms.
| Arm | Measure | Group | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol | Plasma Levels of IL-6 and IL-8 on Study Day 3 | IL6 | 1.9 pg/ml | Standard Deviation 0.6 |
| Albuterol | Plasma Levels of IL-6 and IL-8 on Study Day 3 | IL8 | 1.7 pg/ml | Standard Deviation 0.5 |
| Placebo | Plasma Levels of IL-6 and IL-8 on Study Day 3 | IL6 | 1.8 pg/ml | Standard Deviation 0.7 |
| Placebo | Plasma Levels of IL-6 and IL-8 on Study Day 3 | IL8 | 1.7 pg/ml | Standard Deviation 0.5 |
Secondary
Ventilator Free Days to Day 28 in the Subset of Participants With ARDS
Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200). P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2. VFD to Day 28 is defined as the number of days from the end of ventilation to day 28 in patients who maintained unassisted breathing for at least two consecutive calendar days. Patients who died before day 28 were assigned a VFD count of zero. If a patient returned to assisted breathing, subsequently required assisted breathing, and once again achieved unassisted breathing, only the VFDs after beginning the final period of unassisted breathing were counted. An increase in the number of VFDs was considered a positive result.
Time frame: Determined 28 days after a subject entered the study
Population: Patients meeting the criteria for ARDS (pre-randomization PaO2/FiO2 ratio less than or equal to 200) were selected for this subset.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol | Ventilator Free Days to Day 28 in the Subset of Participants With ARDS | 14.5 days | Standard Error 1.1 |
| Placebo | Ventilator Free Days to Day 28 in the Subset of Participants With ARDS | 16.8 days | Standard Error 1 |
p-value: 0.1395% CI: [-5.3, 0.6]ANCOVA
Secondary
Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock
Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure\<60 or the need for vasopressors (except dopamine \<6 ug/kg/min).
Time frame: Determined 28 days after a subject entered the study
Population: Patients with protocol defined shock (mean arterial pressure\<60 or need for vasopressors except dopamine \< 6ug/kg/min) at the time of study entry.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol | Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock | 10.0 days | Standard Error 1.3 |
| Placebo | Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock | 13.9 days | Standard Error 1.4 |
p-value: 0.04895% CI: [-7.8, 0]ANCOVA