Clinical trial NCT00434993: Drug Study of Albuterol to Treat Acute Lung Injury
Official title: Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo in Acute Lung Injury
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Respiratory Distress Syndrome, Adult
Keywords: Acute Lung Injury
Acute Respiratory Distress Syndrome
Albuterol
Aerosolized
Critical Care
Ventilator
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
First posted: 2007-02-14
Enrollment: 282
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Ventilator Free Days (VFD)
timeFrame: Determined 28 days after a subject entered the study
Secondary outcomes:
measure: Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60
timeFrame: Determined 60 days after a subject entered the study
measure: Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90
timeFrame: Determined 90 days after a subject entered the study
measure: Number of ICU-free Days at 28 Days After Randomization
timeFrame: Determined 28 days after a subject entered the study
measure: Number of Organ Failure-free Days at Day 28 Following Randomization
timeFrame: Daily from baseline to study day 28
measure: Ventilator Free Days to Day 28 in the Subset of Participants With ARDS
timeFrame: Determined 28 days after a subject entered the study
measure: Hospital Mortality to Day 60 in the Subset of Participants With ARDS
timeFrame: Determined 60 days after a subject entered the study
measure: Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock
timeFrame: Determined 28 days after a subject entered the study
measure: Hospital Mortality up to Day 60 in Subjects With Baseline Shock
timeFrame: Determined 60 days after a subject entered the study
measure: Plasma Levels of IL-6 and IL-8 on Study Day 3
timeFrame: Measured at baseline and 3 days after randomization
Other outcomes:
Locations:
city: Fresno
country: United States
facility: University of San Francisco-Fresno Medical Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF-Moffitt Hospital
state: California
city: San Francisco
country: United States
facility: UCSF-San Francisco General Hospital
state: California
city: Denver
country: United States
facility: Centura St. Anthony Central Hospital
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: Denver
country: United States
facility: Rose Medical Center
state: Colorado
city: Denver
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Washington DC
country: United States
facility: Washington Hospital Center
state: District of Columbia
city: Baton Rouge
country: United States
facility: Baton Rouge General Hospital-Blue Bonnet
state: Louisiana
city: Baton Rouge
country: United States
facility: Baton Rouge General Hospital-Midcity
state: Louisiana
city: Baton Rouge
country: United States
facility: Earl K. Long Medical Center
state: Louisiana
city: Baton Rouge
country: United States
facility: Our Lady of the Lake Regional Medical Center
state: Louisiana
city: New Orleans
country: United States
facility: Medical Center of Louisiana
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Baltimore VA Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Bayview Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Baltimore
country: United States
facility: University of Maryland Shock Trauma Center
state: Maryland
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Rochester Methodist Hospital
state: Minnesota
city: Rochester
country: United States
facility: St. Mary's Hospital, Mayo Clinic
state: Minnesota
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Durham
country: United States
facility: Durham Regional Medical Center
state: North Carolina
city: Greensboro
country: United States
facility: Moses Cone Health System
state: North Carolina
city: Greensboro
country: United States
facility: Wesley Long Community Hospital
state: North Carolina
city: Winston Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Ogden
country: United States
facility: McKay-Dee Hospital
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Medical Center
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of California, San Francisco
name: Michael A. Matthay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Roy Brower, MD
role: STUDY_CHAIR
References:
citation: Brown SM, Wilson E, Presson AP, Zhang C, Dinglas VD, Greene T, Hopkins RO, Needham DM; with the National Institutes of Health NHLBI ARDS Network. Predictors of 6-month health utility outcomes in survivors of acute respiratory distress syndrome. Thorax. 2017 Apr;72(4):311-317. doi: 10.1136/thoraxjnl-2016-208560. Epub 2016 Jul 20.
citation: Ambrus DB, Benjamin EJ, Bajwa EK, Hibbert KA, Walkey AJ. Risk factors and outcomes associated with new-onset atrial fibrillation during acute respiratory distress syndrome. J Crit Care. 2015 Oct;30(5):994-7. doi: 10.1016/j.jcrc.2015.06.003. Epub 2015 Jun 16.
citation: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, Holets S, Kallet RH, Liu KD, MacIntyre N, Moss M, Schoenfeld D, Steingrub J, Thompson BT. Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011 Sep 1;184(5):561-8. doi: 10.1164/rccm.201012-2090OC.