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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01715883
Recruitment Status : Terminated (Lack of support staff)
First Posted : October 29, 2012
Last Update Posted : August 23, 2017
Information provided by (Responsible Party):
Matthew Morrell, University of Pittsburgh

Brief Summary:
This is a Phase IIA observational nonrandomized pilot investigation to evaluate the safety and efficacy of Sodium Nitrite administration for the reduction of PGD in patients undergoing lung transplant. The study will enroll 8 subjects, undergoing lung transplant at the University of Pittsburgh Medical Center (UPMC).

Condition or disease Intervention/treatment Phase
Primary Graft Dysfunction Drug: Sodium Nitrite Phase 2

Detailed Description:

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, Sodium Nitrite Injection USP (30mg/mL) NDC Number 60267-079-02) 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 IIA 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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Sodium Nitrite Administration at the Time of Lung Organ Procurement and Transplantation to Minimize the Risk of Pulmonary Graft Dysfunction
Study Start Date : October 2011
Actual Primary Completion Date : May 2017
Actual Study Completion Date : May 2017

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Sodium Nitrite

Sodium Nitrite will be administered at three time points:

At the time of organ procurement, a pre-prepared syringe of sodium nitrite will be added to each of the 2.8L bags of Perfadex solution to flush the donor lungs.

At the time of transplant just prior to reperfusion of lungs, , the donor lungs are flushed with a cold pneumoplegia solution after the bronchial (1st) anastomosis and with warm pneumoplegia solution after the PV (3rd, last) anastomosis. The drug will be added to pneumoplegia solution just prior to both the flushes.

Sodium Nitrite will be delivered intravenously to the recipient immediately prior to lung reperfusion as a single infusion at rate of 4 mL/min for the first 30 min, followed by 2.2 mL/min for the next 60 min.

Drug: Sodium Nitrite
Same as the details in Arm Description.
Other Name: NDC Number 60267-079-02

Primary Outcome Measures :
  1. Incidence of grades 2+3 PGD grade during the first 72 hours post organ reperfusion. [ Time Frame: First 72 hours post organ reperfusion. ]
    The primary study endpoint is the incidence of grades 2+3 PGD based upon the worst PGD grade during the first 72 hours post organ reperfusion (T0-72 or D0-D3).

Secondary Outcome Measures :
  1. Incidence of Methemoglobinemia during Nitrite infusion to the transplant [ Time Frame: 5, 30, and 60 minutes during the infusion; and at 5, 10, 30, 60, 90, 150 after the infusion. ]
    The safety of Sodium Nitrite administration will be assessed by measurement of methemoglobin levels during and after the nitrite infusion in the transplant recipient.

  2. Incidence of fall in patient's mean arterial pressure greater than 20% from recorded baseline requiring discontinuation of drug infusion. [ Time Frame: Monitored at 1 minute intervals during study drug infusion followed by 15 minute intervals for 1 hour. ]
    The safety of Sodium Nitrite administration will be assessed by change in mean arterial pressure greater than 20% from recorded baseline during and after the nitrite infusion in the transplant recipient.

  3. Incidence of acute and Chronic rejection [ Time Frame: Up to 12 months post Lung transplan ]
    To evaluate the efficacy of Sodium Nitrite infusion into the procured lungs and the lung transplant recipient in the prevention of delayed allograft complications including the incidence of acute and chronic rejection. Prevention of delayed allograft complications include clinically indicated spirometric and lung volume assessments of lung function performed as an indicator of Bronchiolitis Obliterans Syndrome (BOS), and evidence of pathological rejection by surveillance transbronchial lung biopsies.

Other Outcome Measures:
  1. Number of Ventilator Free Days (VFD) [ Time Frame: 8am through D30 post transplantation. ]
    Defined as the number of days off mechanical ventilation at 8am through D30 post transplantation.

  2. Number of ICU Free Days (IFD) [ Time Frame: Days outside the ICU through D30 post transplantation. ]
    Defined as the number of days outside the ICU through D30 post transplantation.

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
    • PaO2/FiO2 (O2 challenge) < 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 PAH, or secondary PAH with mean PA > 30 mm Hg)
  • Recipient history of abnormal cardiac function defined as prior CABG or LVEF < 45 %
  • Recipient history of open thoracotomy/prior pleurodesis as exclusion criteria. However patients who have had limited VATS 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 BSA
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01715883

United States, Pennsylvania
University of pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Gladwin, Mark, MD
Principal Investigator: Matthew Morrell, MD University of Pittsburgh


Responsible Party: Matthew Morrell, Assistant Professor, Department of Medicine, Division of Pulmonary, Allergy and Critical care medicine, University of Pittsburgh Identifier: NCT01715883     History of Changes
Other Study ID Numbers: PRO11030251
First Posted: October 29, 2012    Key Record Dates
Last Update Posted: August 23, 2017
Last Verified: August 2017

Keywords provided by Matthew Morrell, University of Pittsburgh:
Lung transplant
Pulmonary Graft Dysfunction
Sodium Nitrite

Additional relevant MeSH terms:
Primary Graft Dysfunction
Reperfusion Injury
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Pathologic Processes