The BOLD Study

Beta-agonists for Oxygenation in Lung Donors

Background

• Demand for donor lungs exceeds the available supply

• Donor hypoxemia and radiographic infiltrates are common reasons for rejection of lungs for transplantation

• Pulmonary edema is a common cause of hypoxemia and pulmonary infiltrates in brain dead organ donors

The majority of organ donors have some degree of pulmonary edema

010203040506070

Percent of Patients

Degree of Pulmonary Edema

None (< 4.2)Mild (4.2-5.0)Moderate/severe (>5.0)

Mean Wet to Dry Ratio 4.4 ± 0.6 in 29 organ donors whose lungs were rejected for transplantation

Lancet 2002; 360: 619-20

Alveolar fluid clearance is intact in the majority of lungs rejected for transplantation

0

20

40

60

80

100

Percent of Lungs

Alveolar Fluid Clearance

Impaired < 3%/hIntact ≥ 3%/h

Mean Alveolar Fluid Clearance 4.7 ± 2.4 %/h

Lancet 2002; 360: 619-20

A beta-adrenergic agonist increases the rate of alveolar fluid clearance in human donor lungs

J Appl Physiol 2002; 93:1869

Aerosolized albuterol given via the ventilator circuit reaches therapeutic concentrations (10-6 M) in the distal airspaces

Intensive Care Med 2002;28:705

BOLD Study Hypothesis

Administration of an inhaled beta-adrenergic agonist (albuterol) will:

1. improve donor oxygenation (primary endpoint)

2. Improve lung compliance and CXR3. improve donor lung utilization rates4. Improve pulmonary edema as measured

in resected lungs5. Improve recipient outcomes

Investigators and Study Personnel

Vanderbilt: Lorraine Ware, Minerva Covarrubias, Nancy Wickersham,

UCSF: Michael Matthay, Sandy Brady, Jae Woo Lee, Jenny Fang

CTDN: Megan Landeck, Eugene Osborne, Ben Chau, Cynthia Ison, the Transplant Coordinators and the APCs

Inclusion and Exclusion Criteria

Inclusion Criteria:- Brain death- Consent for research from family- Donor ≥ 14 years of age- Coroner release for lungs to be used for research for Matthay’s lab

Exclusion Criteria:- CNP donors (Consent Not Productive) will not be included in final analysis

Study Design

• Randomized double blinded design:– Albuterol 5.0 mg aerosolized q4h vs. placebo– Intervention begins immediately when care of donor is

assumed by CTDN

0 1 5 9 13 17 21 25 29

Baseline history, chest X-ray, arterial blood gas and blood samples

Static lung compliance every 12 hours

Study drug q 4h until organ procurement or 72 h

Repeat chest x-ray, arterial blood gas and blood samples. Recover lungs for laboratory evaluation if not transplanted

Organ Procure-

mentTime(h)

Enr

ollm

ent

Stu

dy D

rug

Stu

dy D

rug

Stu

dy D

rug

Stu

dy D

rug

Stu

dy D

rug

Stu

dy D

rug

Stu

dy D

rug

Stu

dy D

rug

Study Update

• Enrollment began in late April 2007• 78 Donors have been enrolled (12 CNP)• No change in overall donor lung utilization

rates• Lungs from 33 donors procured for

measurement of lung water (Matthay lab)

Adverse Event Monitoring

• Heart rate and rhythm monitored after every dose of study drug

• Study drug dose reduced (1/2) in two donors due to tachycardia

• Study drug stopped in one donor due to tachycardia

• No arrhythmias other than sinus tachycardia• No Serious Adverse Events

Looking Ahead

• Targeted enrollment: 500 organ donors• Anticipated monthly enrollment ~ 12 donors• Anticipate 36 additional months for full targeted

enrollment• DSMB for safety and efficacy at 100 and 300

donors• Study can be stopped early for efficacy

Special Thanks to:

• Megan Landeck• The transplant coordinators and APCs• The HLA labs at UCSF, CPMC and

Stanford• NIH NHLBI--R01 funding anticipated 01/08

The BOLD Study

Beta-agonists for Oxygenation in Lung Donors