ALTA: Drug Study of Albuterol to Treat Acute Lung Injury

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00434993
• Collaborator: (none)
• Enrollment: 282
• Locations: 40
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Respiratory Distress Syndrome, Adult	Drug: Albuterol Sulfate; Procedure: Mini-Bronchoalveolar Lavage (BAL); Drug: Placebo	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 282 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo in Acute Lung Injury
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Albuterol Sulfate	Drug: Albuterol Sulfate; 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.; Other Names: 0.9% sodium chloride ; Procedure: Mini-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; Other Names: Combicath
Placebo Comparator: Placebo	Procedure: Mini-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; Other Names: Combicath ; Drug: Placebo; 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.; Other Names: 0.9% sodium chloride

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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).

8. 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).

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of San Francisco-Fresno Medical Center	Fresno	California	United States
2	University of California, Davis Medical Center	Sacramento	California	United States
3	UCSF-Moffitt Hospital	San Francisco	California	United States
4	UCSF-San Francisco General Hospital	San Francisco	California	United States
5	Centura St. Anthony Central Hospital	Denver	Colorado	United States
6	Denver Health Medical Center	Denver	Colorado	United States
7	Rose Medical Center	Denver	Colorado	United States
8	University of Colorado Health Sciences Center	Denver	Colorado	United States
9	Washington Hospital Center	Washington DC	District of Columbia	United States
10	Baton Rouge General Hospital-Blue Bonnet	Baton Rouge	Louisiana	United States
11	Baton Rouge General Hospital-Midcity	Baton Rouge	Louisiana	United States
12	Earl K. Long Medical Center	Baton Rouge	Louisiana	United States
13	Our Lady of the Lake Regional Medical Center	Baton Rouge	Louisiana	United States
14	Medical Center of Louisiana	New Orleans	Louisiana	United States
15	Ochsner Clinic Foundation	New Orleans	Louisiana	United States
16	Tulane University Health Sciences Center	New Orleans	Louisiana	United States
17	Baltimore VA Medical Center	Baltimore	Maryland	United States
18	Johns Hopkins Bayview Medical Center	Baltimore	Maryland	United States
19	Johns Hopkins Hospital	Baltimore	Maryland	United States
20	University of Maryland Shock Trauma Center	Baltimore	Maryland	United States
21	Baystate Medical Center	Springfield	Massachusetts	United States
22	Rochester Methodist Hospital	Rochester	Minnesota	United States
23	St. Mary's Hospital, Mayo Clinic	Rochester	Minnesota	United States
24	University of North Carolina	Chapel Hill	North Carolina	United States
25	Duke University Medical Center	Durham	North Carolina	United States
26	Durham Regional Medical Center	Durham	North Carolina	United States
27	Moses Cone Health System	Greensboro	North Carolina	United States
28	Wesley Long Community Hospital	Greensboro	North Carolina	United States
29	Wake Forest University Baptist Medical Center	Winston Salem	North Carolina	United States
30	Cleveland Clinic Foundation	Cleveland	Ohio	United States
31	MetroHealth Medical Center	Cleveland	Ohio	United States
32	University Hospitals of Cleveland	Cleveland	Ohio	United States
33	Vanderbilt University Medical Center	Nashville	Tennessee	United States
34	Baylor College of Medicine	Houston	Texas	United States
35	McKay-Dee Hospital	Ogden	Utah	United States
36	Utah Valley Regional Medical Center	Provo	Utah	United States
37	LDS Hospital	Salt Lake City	Utah	United States
38	University of Virginia Medical Center	Charlottesville	Virginia	United States
39	Harborview Medical Center	Seattle	Washington	United States
40	University of Washington	Seattle	Washington	United States

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Michael A. Matthay, MD, University of California, San Francisco
• Study Chair: Roy Brower, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NHLBI Acute Respiratory Distress Syndrome Network Website

Publications

None provided.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT00434993
• Other Study ID Numbers: 474; N01 HR056179; HHSN268200536179C
• First Posted: Feb 14, 2007
• Last Update Posted: Feb 10, 2017
• Last Verified: Dec 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Heart, Lung, and Blood Institute (NHLBI): Acute Lung Injury; Acute Respiratory Distress Syndrome; Albuterol; Aerosolized; Critical Care; Ventilator
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Lung Injury; Acute Lung Injury; Albuterol

Study Results

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.

Arm/Group Title	Albuterol Sulfate	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Period Title: Overall Study
STARTED	152	130
COMPLETED	152	130
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Albuterol Sulfate	Placebo	Total
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours	Total of all reporting groups
Overall Participants	152	130	282
Age (Count of Participants)
<=18 years	2 1.3%	3 2.3%	5 1.8%
Between 18 and 65 years	111 73%	100 76.9%	211 74.8%
>=65 years	39 25.7%	27 20.8%	66 23.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.3 (16.4)	50.9 (16.2)	51.6 (16.2)
Gender (Count of Participants)
Female	67 44.1%	59 45.4%	126 44.7%
Male	85 55.9%	71 54.6%	156 55.3%
Region of Enrollment (participants) [Number]
United States	152 100%	130 100%	282 100%

Outcome Measures

1. Primary Outcome

Title	Number of Ventilator Free Days (VFD)
Description	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

Outcome Measure Data

Analysis Population Description

All the intent to treat patients were analyzed. Data was available on all subjects for the primary analysis only.

Arm/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	152	130
Mean (Standard Error) [days]	14.4 (0.9)	16.6 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.087
	Comments	The p-value was not adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline shock.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -4.7 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.3
	Estimation Comments

2. Secondary Outcome

Title	Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat population.

Arm/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	152	130
Number [percentage of participants who died]	23.0 15.1%	17.7 13.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.302
	Comments	The p-value was not adjusted for multiple comparisons.
	Method	Regression, Logistic
	Comments	Adjusted for baseline shock.
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 95%; -4.0 to 14.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat.

Arm/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	152	130
Number [percentage of participants who died]	24.3 16%	18.5 14.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.261
	Comments	The p-value was not adjusted for multiple comparisons.
	Method	Regression, Logistic
	Comments	Adjusted for baseline shock.
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	5.9
	Confidence Interval	(2-Sided) 95%; -3.7 to 15.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of ICU-free Days at 28 Days After Randomization
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat.

Arm/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	152	130
Mean (Standard Error) [days]	13.5 (0.8)	16.2 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	The p-value was not adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline shock.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -4.9 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Organ Failure-free Days at Day 28 Following Randomization
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat.

Arm/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	152	130
Mean (Standard Error) [days]	14.2 (0.9)	15.9 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.226
	Comments	The p-value was not adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline shock.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -4.3 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Ventilator Free Days to Day 28 in the Subset of Participants With ARDS
Description	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

Outcome Measure Data

Analysis Population Description

Patients meeting the criteria for ARDS (pre-randomization PaO2/FiO2 ratio less than or equal to 200) were selected for this subset.

Arm/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	106	86
Mean (Standard Error) [days]	14.5 (1.1)	16.8 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.130
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline shock.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -5.3 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Hospital Mortality to Day 60 in the Subset of Participants With ARDS
Description	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

Outcome Measure Data

Analysis Population Description

Patients meeting the criteria for ARDS (pre-randomization PaO2/FiO2 ratio less than or equal to 200) were selected for this subset.

Arm/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	106	86
Number [percentage of participants who died]	24.5 16.1%	16.3 12.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.176
	Comments
	Method	Regression, Logistic
	Comments	Adjusted for baseline shock.
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	8.2
	Confidence Interval	(2-Sided) 95%; -3.1 to 19.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	68	55
Mean (Standard Error) [days]	10.0 (1.3)	13.9 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.9
	Confidence Interval	(2-Sided) 95%; -7.8 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Hospital Mortality up to Day 60 in Subjects With Baseline Shock
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	68	55
Number [percentage of participants who died]	36.8 24.2%	27.3 21%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.265
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	9.5
	Confidence Interval	(2-Sided) 95%; -6.9 to 25.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Plasma Levels of IL-6 and IL-8 on Study Day 3
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Albuterol	Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Preservative-free 0.9% sterile sodium chloride every 4 hours
Measure Participants	127	110
IL6	1.9 (0.6)	1.8 (0.7)
IL8	1.7 (0.5)	1.7 (0.5)

Adverse Events

Arm/Group Title	Albuterol Sulfate		Placebo
Arm/Group Description	Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours		Preservative-free 0.9% sterile sodium chloride every 4 hours
All Cause Mortality
	Albuterol Sulfate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Albuterol Sulfate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/152 (0.7%)		1/130 (0.8%)
Respiratory, thoracic and mediastinal disorders
Hypoxemia	0/152 (0%)	0	1/130 (0.8%)	1
Hypoxia	1/152 (0.7%)	1	0/130 (0%)	0
Other (Not Including Serious) Adverse Events
	Albuterol Sulfate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/152 (13.8%)		15/130 (11.5%)
Cardiac disorders
Arrhythmias (clinically important)	15/152 (9.9%)	29	8/130 (6.2%)	11
Metabolism and nutrition disorders
Hypokalemia	8/152 (5.3%)	12	7/130 (5.4%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.