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 Mean Wet to Dry Ratio 4.4 ± 0.6 in 29 organ donors whose lungs were rejected for transplantation Lancet 2002; 360:

Alveolar fluid clearance is intact in the majority of lungs rejected for transplantation Mean Alveolar Fluid Clearance 4.7 ± 2.4 %/h Lancet 2002; 360:

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: –Albuterol 5.0 mg aerosolized q4h vs. placebo –Intervention begins immediately when care of donor is assumed by CTDN 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- ment Time (h) Enrollment Study Drug

Study Update Enrollment began in late April 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