Safety and Efficacy Study of Nitric Oxide in Patients Going Through Lung Transplantation

A Pilot, Single Center Prospective, With Parallel Groups, Controlled and Open to Evaluate the Efficacy of Nitric Oxide for Inhalation in Lung Donors and in the Prevention of Reperfusion Injury.

The purpose of this study is to assess the safety and efficacy of inhaled nitric oxide in prevention of lung graft dysfunction due to ischemia-reperfusion

Study Overview

• Status: Completed
• Conditions: Lung Transplantation
• Intervention / Treatment: Drug: Nitric oxide; Drug: Nitric oxide

Detailed Description

• Pilot, single-center, prospective, randomized, parallel-group, controlled, open-label trial.
• Sixty lung donors will be analyzed, making a comparative study between donors receiving NO for 3 hours prior to removal of the organ versus a control group to which NO will not be administered.
• A Swan-Ganz catheter will be placed to determine PVR, PAP, MV, and PCP; and blood gases will be done after arterial cannulation to determine FiO2/PaO2 hourly. Also, standard blood chemistry, hematology, coagulation parameters, and arterial blood gas.
• Prior to NO administration and before procurement, a BAL (bronchoalveolar lavage) will be done to determine the presence of leukocytes, predominantly neutrophils, IL-1, IL-6, IL-8, IL-10, TNF, and proteins as well as obtaining secretions for culture.
• The dosage of NO will be 10ppm, with NO2 and methemoglobinemia being monitored exhaustively.
• In the operating room and prior to lung removal, a new BAL will be done and the anti-inflammatory agents described above will be determined.
• Organ removal and the preservation fluid used will be standard, according to the established surgical protocol.
• Anesthesia: methylprednisolone 1 g will be administered before organ extraction; hemodynamic determinations of mAP, PAP, CVP, MV, and hourly urinary output and arterial blood gas.
• Hemodynamic and respiratory determinations will be made in the lung receptors: mAP, mPAP, PVR, MV, PCP, DO2, Qs/Qt, and CVP as well as gas determinations every 30 minutes, blood chemistry, hematology, and coagulation immediately after reperfusion. A BAL will also be done after anesthesia induction.
• Incidents during surgery will be recorded, especially the need for extracorporeal circulation as well as transfusion requirements and ischemia times.
• After surgery, another BAL will be done both 24 hours and 48 hours after return to the Recovery Unit. Hemodynamic and respiratory parameters will be monitored every 4 hours for the first 48 hours after surgery, as well as arterial blood gases.
• Blood chemistry will be done every 12 hours along with coagulation and hematology tests.
• Chest x-ray on admission and daily to determine the degree of the patient's edema over the first 48 hours.
• Drug administration: the NO will be administered in the respirator intake at a dose of 10ppm for 48 hours. A monitor will be used showing the gas dosage continuously, as well as NO2 and methemoglobinemia.
• The inflammatory agents (TNF, IL-1, IL-2, IL-6, IL-8, and IL-10) will be determined with the ELISA technique.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Valencia, Spain, 46009
    • Hospital General La Fe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have a lung graft scheduled
• Males and females aged 18 to 65
• Signed informed consent approved by the IRB/EC

Exclusion Criteria:

• Uncontrolled bacterial infection
• Creatinine clearance <50 ml/min
• Severe extrapulmonary organic dysfunction
• Continuing smoking habit
• Neoplastic disease (2-5 years free of tumor, depending on type)
• Pregnancy or nursing
• Severe osteoporosis
• Active peptic ulcer
• Progressive neuromuscular disease
• Active limiting systemic disease. Complicated diabetes.
• Any contraindication based on the judgement of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: A; Neither donors or recipients will receive NO
Active Comparator: B; Donor will not receive NO, recipient will receive up to 48 hours of NO	Drug: Nitric oxide; inhalation, 10 ppm, for up to 48 hours; Drug: Nitric oxide; inhalation; 10ppm; 3 hours (donor) up to 48 hours (recipient)
Active Comparator: C; The donor will receive NO for 3 hours and the recipient will receive NO for up to 48 hours	Drug: Nitric oxide; inhalation, 10 ppm, for up to 48 hours; Drug: Nitric oxide; inhalation; 10ppm; 3 hours (donor) up to 48 hours (recipient)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Edema and mPAP	4 - 48 hours

Collaborators and Investigators

• Sponsor: Mallinckrodt
• Investigators: Principal Investigator: Rosario Vicente, MD, Hospital General La Fe

Publications and helpful links

General Publications

• Moreno I, Vicente R, Ramos F, Vicente JL, Barbera M. Determination of interleukin-6 in lung transplantation: association with primary graft dysfunction. Transplant Proc. 2007 Sep;39(7):2425-6. doi: 10.1016/j.transproceed.2007.07.056.
• Moreno I, Mir A, Vicente R, Pajares A, Ramos F, Vicente JL, Barbera M. Analysis of interleukin-6 and interleukin-8 in lung transplantation: correlation with nitric oxide administration. Transplant Proc. 2008 Nov;40(9):3082-4. doi: 10.1016/j.transproceed.2008.08.124.
• Moreno I, Vicente R, Mir A, Leon I, Ramos F, Vicente JL, Barbera M. Effects of inhaled nitric oxide on primary graft dysfunction in lung transplantation. Transplant Proc. 2009 Jul-Aug;41(6):2210-2. doi: 10.1016/j.transproceed.2009.05.019.

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: December 6, 2007
• First Submitted That Met QC Criteria: December 6, 2007
• First Posted (Estimate): December 10, 2007

Study Record Updates

• Last Update Posted (Estimate): October 19, 2016
• Last Update Submitted That Met QC Criteria: October 18, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Lung transplantation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: VICER1