Transcript High Prevalence of Pulmonary Arterial Thrombi in Donor Lungs

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
70
60
None (< 4.2)
Mild (4.2-5.0)
Moderate/severe (>5.0)
50
Percent of 40
Patients 30
20
10
0
Degree of Pulmonary Edema
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
Impaired < 3%/h
Intact ≥ 3%/h
100
80
Percent 60
of Lungs
40
20
0
Alveolar Fluid Clearance
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 CXR
3. improve donor lung utilization rates
4. Improve pulmonary edema as measured
in resected lungs
5. 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:
1
9
13
17
21
Study Drug
Study Drug
Study Drug
Study Drug
Study Drug
Study Drug
5
25
Study Drug
0
Study Drug
Enrollment
– Albuterol 5.0 mg aerosolized q4h vs. placebo
– Intervention begins immediately when care of donor is
assumed by CTDN
Study drug q 4h until
organ procurement or
72 h
29
Organ
Procurement
Time
(h)
Baseline history, chest Xray, arterial blood gas and
blood samples
Static lung compliance every 12
hours
Repeat chest x-ray, arterial blood
gas and blood samples.
Recover lungs for laboratory
evaluation if not transplanted
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