Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02885636
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 12
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

The enormous and rapidly growing burden of Heart Failure with Preserved Ejection Fraction (HFpEF) has led to a need to understand the pathogenesis and treatment options for this morbid disease. Recent research from the investigator's group and others have shown that pulmonary hypertension (PH) is highly prevalent in HFpEF, and right ventricular (RV) dysfunction is present in both early and advanced stages of HFpEF.

These abnormalities in the RV and pulmonary vasculature are coupled with limitations in pulmonary vasodilation during exercise. There are no therapies directly targeted at the pulmonary vasculature that have been clearly shown to be effective in HFpEF. A recent study by Mayo Clinic Investigators has demonstrated pulmonary vasodilation with dobutamine (a beta 2 agonist) in HFpEF. As an intravenous therapy, this is not feasible for outpatient use.

In the proposed randomized, placebo-controlled double blinded trial, the investigators seek to evaluate whether the commonly used inhaled bronchodilator albuterol (a beta 2 agonist), administered through a high-efficiency nebulizer device that achieves true alveolar drug delivery, improves pulmonary vascular resistance (PVR) at rest and during exercise in patients with HFpEF as compared to placebo. This has the potential to lead to a simple cost effective intervention to improve symptoms in HFpEF, and potentially be tested in other World Health Organization (WHO) Pulmonary Hypertension groups. PVR is an excellent surrogate marker for pulmonary vasodilation and has been used in previous early trials of PH therapy.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure; Heart Failure, Left-Sided; Left-Sided Heart Failure	Drug: Albuterol; Other: Saline placebo	Phase 3

Detailed Description

Preliminary studies to support feasibility: Recent research from the investigator's group has shown that right ventricular (RV) dysfunction is present in a third of patients with HFpEF and the presence of pulmonary vascular disease and pulmonary hypertension (PH) is very high (related to both pulmonary venous hypertension as well as pulmonary vascular disease). Both of these have been associated with adverse outcomes and exercise intolerance but no therapy is currently available directly targeted at the pulmonary vasculature in HFpEF.

The investigators recently demonstrated significant improvements in pulmonary vascular function with dobutamine (a β2 agonist) administered acutely in HFpEF. As an intravenous therapy, this is not suitable for chronic outpatient use. Hospitalized patients with heart failure often demonstrate symptomatic improvement with inhaled β2 agonist therapy, even in the absence of pulmonary disease, and animal studies have also shown improved resolution of pulmonary edema with albuterol. In the proposed randomized, double blinded placebo-controlled trial, the investigators seek to evaluate whether the commonly used inhaled bronchodilator albuterol, administered through a high-efficiency nebulizer device, improves pulmonary vascular function in patients with HFpEF-PH as compared to placebo. This has the potential to lead to a simple cost effective intervention to improve symptoms in HFpEF-PH, and potentially be tested in other WHO PH groups.

In the absence of frank signs of congestive heart failure, patients with early HFpEF can only be reliably diagnosed by exercise right heart catheterization, which is routinely performed at Mayo Clinic as part of the evaluation of patients with unexplained dyspnea. The presence of elevated pulmonary capillary wedge pressures (PCWP) at rest (>15 mmHg) or with exercise (>25 mmHg); and elevated mean pulmonary artery pressures at rest (>25 mm Hg) and with exercise (>40 mmHg) has been used to invasively diagnose HFpEF with exercise pulmonary hypertension with a high degree of validity and reliability. Just as exercise stress unmasks abnormalities in left ventricular (LV) diastolic function in early stage HFpEF, the investigators have very recently shown that exercise stress reveals early abnormalities in pulmonary artery vascular function as compared to controls without HF that are not apparent from resting data alone.

Using objective diagnoses of HFpEF and exercise induced PH, the investigators seek to evaluate the hemodynamic changes with exercise in pulmonary vascular resistance, peak cardiac output and subjective dyspnea before and after inhaled albuterol therapy for pulmonary vasodilation.

Study design: This study will be performed in a randomized, double blind placebo-controlled fashion using inhaled albuterol or inhaled saline (prepared by research pharmacy) administered through a novel high-efficiency nebulizer in a 1:1 fashion. Patients will undergo right heart catheterization (RHC) with expired-gas analysis using high Fidelity micromanometer catheters at rest and with exercise, at baseline and following treatment with study drug, using a novel study design that the investigators have previously utilized and reported. Rest and exercise measurements will be repeated after receiving inhaled albuterol or control therapy.

Patients referred to the cardiac catheterization laboratory for invasive exercise stress testing will be prospectively recruited. Standard RHC using high fidelity micromanometers (Millar Instruments) will be performed at rest and during supine exercise with simultaneous expired gas analysis (MedGraphics) as is our current practice. The protocol is rest-20 Watts exercise x 5 minutes, and then graded workload increases in 10-20 Watt increments (3 minute stages) to exhaustion. Hemodynamic, arterial and mixed venous blood gas and expired gas data are acquired at rest, during each exercise stage and at peak exercise. Venous blood samples will be obtained at rest and at peak exercise. Perceived symptoms of dyspnea and fatigue will be quantified using the Borg dyspnea and effort scores at each stage of exercise. Limited echocardiography will be performed by a cardiologist skilled in imaging focused on measures of RV morphology and function.

After the initial exercise study and hemodynamics have returned to baseline, study drug (normal saline placebo or albuterol 2.5 mg) will be inhaled through a high efficiency nebulizer over 5 minutes. After a 10 minute observation period, resting hemodynamic and expired gas data will be acquired exactly as in the initial run. Subjects will then repeat the 20 Watt x 5 minutes exercise phase. Subjects will repeat exercise only at the 20 Watt stage, rather repeating the entire study. This is done to increase the feasibility and shorten the time of the case. The investigators have previously observed that the vast majority (>85%) of the elevation in cardiac filling pressures and reduction in venous oxygen content in people with HFpEF occurs at the low 20 Watt workload, so repeating exercise hemodynamic assessment at this load should be sufficient to detect any clinically meaningful treatment effect from albuterol.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial
• Study Start Date: Sep 1, 2016
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose	Drug: Albuterol; : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose; Other Names: Proventil, AccuNeb, Proair, Ventolin, and Vospire
Placebo Comparator: Inhaled saline placebo Inhaled saline through a high efficiency nebulizer -single dose	Other: Saline placebo; Saline inhaled through a nebulizer as a single dose

Outcome Measures

Primary Outcome Measures

1. Change in 20 Watt Exercise Pulmonary Vascular Resistance (PVR) [Baseline, 10 minutes after intervention during exercise]

   The exercise PVR at 20 Watts after study drug relative to the exercise PVR at 20 Watts in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units. A decrease in PVR measured by wood units would be considered a favorable response.

Secondary Outcome Measures

1. Change in Resting Pulmonary Vascular Resistance [Baseline, 10 minutes after intervention]

   The resting PVR after study drug relative to the resting PVR in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units.

2. Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP) [Baseline, 10 minutes after intervention during exercise]

   Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.

3. Change in Resting Pulmonary Capillary Wedge Pressure (PCWP) [Baseline, 10 minutes after intervention]

   Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.

4. Change in Exercise Pulmonary Artery Compliance [Baseline, 10 minutes after intervention during exercise]

   Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.

5. Change in Resting Pulmonary Artery Compliance [Baseline, 10 minutes after intervention]

   Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.

6. Change in Exercise Pulmonary Artery Pressure [Baseline, 10 minutes after intervention during exercise]

   Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.

7. Change in Resting Pulmonary Artery Pressure [Baseline, 10 minutes after intervention]

   Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.

8. Change in Exercise Right Atrial Pressure (RA) [Baseline, 10 minutes after intervention during exercise]

   RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.

9. Change in Resting Right Atrial Pressure (RA) [Baseline, 10 minutes after intervention]

   RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.

10. Change in Exercise Cardiac Output [Baseline, 10 minutes after intervention during exercise]

    Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).

11. Change in Resting Cardiac Output [Baseline, 10 minutes after intervention]

    Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).

12. Change in Exercise Pulmonary Elastance [Baseline, 10 minutes after intervention during exercise]

    Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.

13. Change in Resting Pulmonary Elastance [Baseline, 10 minutes after intervention]

    Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Heart Failure with Preserved Ejection Fraction (HFpEF)

• Normal left ventricular ejection fraction (≥50%)

• Elevated Left Ventricular filling pressures at cardiac catheterization (defined as resting Pulmonary Capillary Wedge Pressure>15 mmHg and/or ≥25 mmHg during exercise).

Exclusion Criteria:

• Prior albuterol therapy (within previous 48 hours)

• Current long acting inhaled beta agonist use

• Significant hypokalemia (<3meq/L)

• Significant valvular disease (>moderate left-sided regurgitation, >mild stenosis)

• High output heart failure

• Severe pulmonary disease

• Unstable coronary disease

• Constrictive pericarditis

• Restrictive cardiomyopathy

• Hypertrophic cardiomyopathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Barry A Borlaug, MD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 21, 2016

More Information

Publications

• Reddy YNV, Obokata M, Koepp KE, Egbe AC, Wiley B, Borlaug BA. The β-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction. Circ Res. 2019 Jan 18;124(2):306-314. doi: 10.1161/CIRCRESAHA.118.313832.

• Responsible Party: Barry Borlaug, Associate Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02885636
• Other Study ID Numbers: 16-005140A; R01HL128526; R01HL126638; U01HL125205; U10HL110262
• First Posted: Aug 31, 2016
• Last Update Posted: Feb 22, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Barry Borlaug, Associate Professor of Medicine, Mayo Clinic: Heart Failure with Preserved Ejection Fraction; Pulmonary Hypertension
• Additional relevant MeSH terms: Heart Failure; Vascular Diseases; Albuterol

Study Results

Participant Flow

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Period Title: Overall Study
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo	Total
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68 (8)	64 (17)	66 (12)
Sex: Female, Male (Count of Participants)
Female	6 40%	8 53.3%	14 46.7%
Male	9 60%	7 46.7%	16 53.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%	15 100%	30 100%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	33.7 (7)	35.6 (9.2)	34.6 (8.1)

Outcome Measures

1. Primary Outcome

Title	Change in 20 Watt Exercise Pulmonary Vascular Resistance (PVR)
Description	The exercise PVR at 20 Watts after study drug relative to the exercise PVR at 20 Watts in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units. A decrease in PVR measured by wood units would be considered a favorable response.
Time Frame	Baseline, 10 minutes after intervention during exercise

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [wood units]	-0.6 (0.5)	0.1 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Change in Resting Pulmonary Vascular Resistance
Description	The resting PVR after study drug relative to the resting PVR in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units.
Time Frame	Baseline, 10 minutes after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [wood units]	-0.6 (0.5)	-0.3 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP)
Description	Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.
Time Frame	Baseline, 10 minutes after intervention during exercise

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg]	-2 (6)	-3 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change in Resting Pulmonary Capillary Wedge Pressure (PCWP)
Description	Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.
Time Frame	Baseline, 10 minutes after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg]	-2 (2)	-2 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change in Exercise Pulmonary Artery Compliance
Description	Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
Time Frame	Baseline, 10 minutes after intervention during exercise

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mL/mm Hg]	1.6 (1.6)	0.0 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Change in Resting Pulmonary Artery Compliance
Description	Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
Time Frame	Baseline, 10 minutes after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mL/mm Hg]	1.2 (1.0)	0.7 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Change in Exercise Pulmonary Artery Pressure
Description	Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time Frame	Baseline, 10 minutes after intervention during exercise

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg]	-8 (4)	-2 (4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Change in Resting Pulmonary Artery Pressure
Description	Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time Frame	Baseline, 10 minutes after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg]	-5 (3)	-3 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Change in Exercise Right Atrial Pressure (RA)
Description	RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time Frame	Baseline, 10 minutes after intervention during exercise

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg]	-5 (3)	-1 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Change in Resting Right Atrial Pressure (RA)
Description	RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time Frame	Baseline, 10 minutes after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg]	-3 (2)	-1 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	t-test, 2 sided
	Comments

11. Secondary Outcome

Title	Change in Exercise Cardiac Output
Description	Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
Time Frame	Baseline, 10 minutes after intervention during exercise

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [L/min]	2.0 (2.1)	0.1 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments

12. Secondary Outcome

Title	Change in Resting Cardiac Output
Description	Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
Time Frame	Baseline, 10 minutes after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [L/min]	0.6 (1.2)	0.4 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7
	Comments
	Method	t-test, 2 sided
	Comments

13. Secondary Outcome

Title	Change in Exercise Pulmonary Elastance
Description	Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
Time Frame	Baseline, 10 minutes after intervention during exercise

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg/mL]	-0.17 (0.11)	-0.05 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments

14. Secondary Outcome

Title	Change in Resting Pulmonary Elastance
Description	Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
Time Frame	Baseline, 10 minutes after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Albuterol	Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose	Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
Measure Participants	15	15
Mean (Standard Deviation) [mm Hg/mL]	-0.11 (0.13)	-0.03 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Albuterol, Inhaled Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Subjects were monitored in the recovery area for up to two hours after procedure.
Arm/Group Title	Inhaled Albuterol		Inhaled Saline Placebo
Arm/Group Description	2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose Albuterol: : Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose		Inhaled saline through a high efficiency nebulizer -single dose Saline placebo: Saline inhaled through a nebulizer as a single dose
All Cause Mortality
	Inhaled Albuterol		Inhaled Saline Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Inhaled Albuterol		Inhaled Saline Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Inhaled Albuterol		Inhaled Saline Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)

Limitations/Caveats

This was a proof-of-concept study and chronic effects of albuterol were not examined. Further studies testing more clinically meaningful end points are needed to determine whether beta-agonists will improve patient-centric outcomes.

More Information

Certain Agreements

All Principal Investigators ARE 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.