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Protocol Number: 01-H-0223 
Patients with sickle cell disease 18 years of age or older may be eligible to participate in one or more parts of this three-stage study. Candidates will be screened with a medical history, physical examination, electrocardiogram, echocardiogram and blood tests. Those enrolled will undergo the following tests and procedures: Stage 1: Patients will be tested to determine the cause of pulmonary hypertension. They will have an echocardiogram (ultrasound study of the heart); a test for asthma, with measurement of arterial blood oxygen levels; oxygen breathing study with measurement of arterial blood oxygen levels; chest X-ray; computed tomography (CT) scans of the lung with and without contrast material; magnetic resonance imaging (MRI) of the heart; 6-minute walk to measure the distance covered in that time at a comfortable pace; night-hawks oxygen measurement while sleeping; blood tests for HIV, hepatitis virus, lupus and arthritis and pregnancy; pulmonary ventilation/perfusion scan with evaluation of shunt fraction to the brain and kidney; and exercise studies will be performed to determine oxygen and carbon dioxide consumption and production and to measure the anaerobic threshold. Stage 2: Patients who proceed with stage 2 will have a detailed MRI evaluation of the heart and will be admitted to the Clinical Center intensive care unit for the following procedure: A small intravenous (IV) catheter (plastic tube) is placed in the patient arm and a longer tube, called a central line, in a deeper neck or leg vein. A long thin tube is then inserted through the vein into the heart and the lung artery to measure all blood pressures in the heart and lungs directly. Following baseline measurements the following medications will be delivered for two hours each, separated by a 30 minute wash-out period. The patients is then given oxygen to breathe for 2 hours, followed by infusion of prostacyclin, a blood pressure-lowering drug, for 2 hours; and finally inhaled nitric oxide for 2 hours. A small blood sample (3 tablespoons) of blood is drawn during the nitric oxide administration. Stage 3: For patients who complete stage II or III and do not respond to NO gas as determined by a decrease in mean or systolic pulmonary artery pressure of greater than 10% from baseline or a 10% increase in 6 minute walk distance, or are unable to receive it due to technical, regulatory (no free standing home structure for storage of NO gas, etc.) or personal lifestyle issues (some patient do not want to carry two tanks of gas - oxygen and NO - or have difficulty learning how to use the NO gas system), we will offer regular exchange transfusions and home oxygen for three months with a goal of maintaining hemoglobin levels of 8-10 and hemoglobin S levels of less than 40%. The monitoring of patients receiving exchange transfusions will be the same as for the patients receiving NO gas: Measurements will include pulmonary artery pressure measured by repeat right heart catheterization, other hemodynamic parameters, exercise tolerance by 6-minute walk, plasma adhesion molecule levels, neutrophil and monocyte mRNA gene profiles, and circulating erythroid progenitor cell a/a hemoglobin message and protein levels. This portion of the study is to be undertaken as an outpatient. Clinical follow-up will involve bi-weekly clinic visits with the principal investigator, associate investigators, or study nurse. At these clinic visits venous blood will be obtained for hemoglobin electrophoresis (including hemoglobin F and A2), CBC, ESR, C-reactive protein and standard chemistries. Research blood, for plasma and erythrocyte reactive nitrogen species and plasma adhesion molecule levels, will be collected with total blood drawn per day not to exceed 30 mL. Protocol nurse or principal investigator will record total weekly symptoms, emergency room visits, hospital admissions, and narcotic use. Echocardiograms and 6-minute walk will be repeated at two-week intervals. 32 mL of blood will be drawn prior to the exchange transfusion and a 4 and 8 weeks for neutrophil and monocyte mRNA expression chip profiling. Patients who develop any complication of their disease (i.e. vaso-occlusive crisis, acute chest syndrome, let ulcers, priapism, avascular necrosis of the femoral hip, asthma, etc.) will be strongly encouraged to directly come to the Clinical Center's 10D ICU for evaluation and direct admission by the 10D ICU physician on-call. If they are very ill they will be instructed to either call and ambulance or go to the nearest emergency room. If they are relatively stable, patients will be instructed to call the 10D ICU and speak with the physician on-call. We will follow patients according to the NO protocol with right heart catheterization at 3 months of therapy and serial echocardiograms. The effects of exchange transfusion will be statistically analyzed separately but in a similar fashion as delineated for NO treatment. All patients will complete Stage I and II of the study prior to entering into Exchange Transfusion therapy. Patients with greater than a 10% increase in six-minute walk distance or a 10% reduction in mean or systolic pulmonary artery pressures, who want to continue Exchange Transfusion therapy will have the option of continuing therapy. In these cases, blood draws and clinical follow-up will be reduced to bi-monthly intervals and when clinically indicated. The Clinical Center will continue to pay for these clinic visits and urgent care at the Clinical Center. The Transfusion Therapy and the Clinical Center care will continue until the study has terminated (anticipated three year study duration). Our physicians and social workers will work with patients to help them obtain appropriate insurance to cover Exchange Transfusion therapy. However, it is possible that circumstances may arise that prevent the patient from continuing this therapy after the study is terminated. Alternative Therapies Patients who have enrolled in the NO or transfusion treatment arm of the study who do not respond to the treatment (defined by a 10% reduction in mean or systolic pulmonary artery pressure measured by right heart catheterization or a 10% increase in 6-minute walk distance) will be eligible to receive the alternative therapy (NO or transfusion) or other FDA approved medications. These medications may include oxygen, prostacyclin (flolan or remodulin), L-arginine, bosentan or sidenafil. We will limit the number of patients who are treated with medication other than NO or exchange transfusion to 10 subjects. Such patients will be managed at the NIH, in collaboration with their primary medical providers, according to accepted current standards of care using only FDA approved medication. The effect of such treatments on estimated pulmonary artery pressures, measured by echocardiogram, and on 6-minute walk distance will be assessed at regular intervals (every 1-3 months while on protocol) and all adverse events reported to the IRB and DSMB as defined by the current protocol. Patients maintained on alternative therapies will not have research bloods drawn, all laboratory testing will be obtained only for clinical indications. Such patients may be managed on this protocol until the protocol is terminated, the medication used becomes FDA approved specifically for use in sickle cell disease, the patient wishes to end participation, or the patient wishes to enroll in another study for treatment of pulmonary hypertension.
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Warren Grant Magnuson Clinical Center (CC)