Sodium Nitrite in Lung Transplant Patients to Minimize the Risk of Pulmonary Graft Dysfunction

While increasing numbers of patients with advanced lung disease are candidates for lung
transplantation, the short- and long-term outcomes are severely compromised by graft
dysfunction, primarily in the form of organ rejection. The earliest manifestation of lung
allograft dysfunction, termed primary graft dysfunction (PGD), represents a form of
ischemia-reperfusion acute lung injury, and occurs in its severest form (Grade 3) in from 10
to 35% of lung transplant recipients 1-6. PGD is the primary cause of early morbidity and
mortality after transplantation and is strongly associated with the late development of
chronic lung rejection or Bronchiolitis Obliterans Syndrome (BOS. Early graft dysfunction
contributes significantly to the suboptimal outcomes of lung transplantation and to the
failure of lung transplant recipients to achieve five-year survival rates comparable to
patients who receive other solid organs such as the heart and liver. The risk of PGD further
limits the time that lungs can be stored ex-vivo, therefore restricting the pool of available
donors. A critical advance in the prevention of both early and late lung allograft
dysfunction will occur if PGD can be successfully prevented or minimized.

In this study, the investigators propose to test the hypothesis that administration of Sodium
Nitrite to donor lungs and lung transplant recipients at the time of transplantation will be
safe and will reduce the incidence of grades 2 and 3 PGD, thereby improving clinical outcomes
with minimal toxicity.

Sodium Nitrite will be obtained from a commercial preparation (Hope Pharmaceuticals) and the
UPMC Pharmacy will prepare the formulations, which will be infused at three time points.
First it will be infused into the preservation solution bag at the time of organ procurement
from the donor, then to the allograft at the time of transplantation, and finally as a direct
infusion into the organ recipient.

The investigators plan to enroll total of 8 subjects undergoing lung transplantation for this
Phase 2 observational non-randomized pilot investigation to evaluate the safety, efficacy,
and pharmacokinetics of Sodium Nitrite administration when administered to the procured lung
and lung transplant recipient, for the prevention of Primary Graft Dysfunction (PGD). It is
anticipated that positive results from this trial lead to a larger clinical investigation of
Sodium Nitrite administration directed at producing a reduction in PGD and perhaps secondary
obliterative bronchiolitis; and will potentially allow for extended organ storage, extended
use of more marginal organs, and more effective use of Donation after Cardiac Death (DCD)
organs which undergo combination of warm and cold ischemia for organ procurement.

Inclusion Criteria:

- Subjects undergoing lung transplantation.

- Subjects in the age range of 18-70 years

- Ability to understand and provide consent. Proxy consent will not be accepted.

Exclusion Criteria:

- Donor exclusion criteria

- Age > 55 years.

- Mechanical ventilation > 5 days prior to procurement

- Significant chest trauma or lung contusion

- Smoking history > 20 pack-year

- Ratio of arterial oxygen partial pressure to fractional inspired oxygen < 300

- Donor radiograph with 2 quadrant infiltrates

- Donor that are determined single lung donors prior to transplant will be excluded.

Recipient exclusion criteria

- Recipient age > 70 years.

- Recipient history of pulmonary hypertension (idiopathic pulmonary arterial
hypertension, or secondary pulmonary arterial hypertension with mean arterial pressure
> 30 mm Hg)

- Recipient history of abnormal cardiac function defined as prior coronary artery bypass
graft (CABG) or left ventricular ejection fraction (LVEF) < 45 %

- Recipient history of open thoracotomy/prior pleurodesis as exclusion criteria. However
patients who have had limited video-assisted thoracic surgery procedures for biopsies
would NOT be excluded from the study.

- Recipient history of cirrhosis

- Recipient history of mechanical ventilation or extracorporeal support pre-operatively

- Recipient pre-operative hypotension defined by a systolic blood pressure less than 90
mm Hg not responsive to intravenous fluids or requirement for vasoactive medications

- Recipient preoperative history of renal insufficiency, dialysis or estimated
glomerular filtration rate <30 ml/min/1.73 m2 body surface area

- Patients undergoing retransplantation

- Recipient history of significant coronary artery disease that is flow limiting and
unable to be corrected by further percutaneous coronary artery interventions.