Drug Study of Albuterol to Treat Acute Lung Injury

Study Overview
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Brief Summary
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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
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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.

Official Title
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Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo in Acute Lung Injury

Conditions
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Respiratory Distress Syndrome, Adult

Intervention / Treatment
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* Drug: Albuterol Sulfate
* Procedure: Mini-Bronchoalveolar Lavage (BAL)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must meet the following three criteria within a 24-hour period: Acute onset of PaO2/FiO2 less than or equal to 300 (adjustments made for altitude where appropriate) Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph 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

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Albuterol Sulfate<br> | Drug: Albuterol Sulfate<br>* 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.<br>* Other names: 0.9% sodium chloride;Procedure: Mini-Bronchoalveolar Lavage (BAL)<br>* 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<br>* Other names: Combicath;|
| Placebo Comparator: Placebo<br> | Procedure: Mini-Bronchoalveolar Lavage (BAL)<br>* 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<br>* Other names: Combicath;Drug: Placebo<br>* 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.<br>* Other names: 0.9% sodium chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Determined 28 days after a subject entered the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Determined 60 days after a subject entered the study | 
| 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. | Determined 90 days after a subject entered the study | 
| 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. | Determined 28 days after a subject entered the study | 
| 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. | Daily from baseline to study day 28 | 
| 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. | Determined 28 days after a subject entered the study | 
| 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. | Determined 60 days after a subject entered the study | 
| 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). | Determined 28 days after a subject entered the study | 
| 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). | Determined 60 days after a subject entered the study | 
| 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. | Measured at baseline and 3 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lung Injury, Acute Respiratory Distress Syndrome, Albuterol, Aerosolized, Critical Care, Ventilator