Nitric Oxide and Transfusion Therapy for Sickle Cell Patients With Pulmonary Hypertension
Nitric Oxide and Transfusion Therapy for Sickle Cell Patients With Pulmonary Hypertension
This study will test whether inhaling nitric oxide (NO) gas mixed with room air can improve
 pulmonary hypertension (high blood pressure in the lungs) in patients with sickle cell
 anemia.

 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, as follows:

 Stage 1

 Patients undergo the following tests to determine the cause of their pulmonary hypertension:
 blood tests; echocardiogram (heart ultrasound); asthma test; oxygen breathing study with
 measurement of arterial blood oxygen levels; chest X-ray; lung scans; MRI of the heart;
 6-minute walk test; night-time oxygen measurement while sleeping; and exercise studies.

 Stage 2

 Patients have a detailed MRI evaluation of the heart and are admitted to the NIH Clinical
 Center intensive care unit (ICU) for the following test: A plastic tube is placed in a vein
 in the patient's arm and another tube is placed in a deeper neck or leg vein. A third tube is
 inserted through the vein into the heart and the lung artery to measure blood pressures in
 the heart and lungs directly. Following baseline measurements, three medications (inhaled
 oxygen, infused prostaglandin, and inhaled NO) are delivered for 2 hours each, separated by a
 30-minute washout period. A small blood sample is drawn during the NO administration.

 Patients who cannot be treated with nitric oxide or for whom the treatment does not work may
 receive monthly exchange transfusions for 3 months. For this procedure, 3 to 5 five units of
 the patient's blood is removed and replaced with 3 to 5 units that do not have sickle
 hemoglobin. Some patients who do not respond to NO or exchange transfusions may receive an
 alternative therapy, such as oxygen, prostacyclin, L-arginine, bosentan or sidenafil.

 Stage 3

 Patients remain in the ICU with catheters in place for another 24 hours. During this time
 they breathe NO. Lung pressures are measured every 4 hours and blood is drawn every 8 hours.
 They then stay in the hospital 1 more day for observation. Patients then breathe nitric oxide
 continuously for 2 months using a tank of gas that delivers the NO through tubes placed in
 the nose. They may do this at home on an outpatient basis or may remain in the hospital for
 the 2 months.

 Patients have an echocardiogram and blood tests every week and do a 6-minute walk test every
 2 weeks....
Sickle cell anemia is an autosomal recessive disorder and the most common genetic disease
 affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for
 sickle cell disease, and 8% have sickle cell trait. Acute pain crisis, acute chest syndrome
 (ACS), and secondary pulmonary hypertension are common complications of sickle cell anemia.
 Pulmonary hypertension has now been identified as a major cause of death in adults with
 sickle cell disease. Inhaled nitric oxide (NO) has been proposed as a possible therapy for
 both primary and secondary pulmonary hypertension. Furthermore, a number of recent studies
 have suggested that NO may have a favorable impact on sickle red cells at the molecular level
 and could improve the abnormal microvascular perfusion that is characteristic of sickle cell
 anemia. In addition, chronic exchange transfusion therapy may reduce the progression and/or
 severity of pulmonary hypertension in these patients.

 This clinical trial is designed (1) to determine the pathophysiologic processes that are
 associated with and potentially contribute to secondary pulmonary hypertension in adult
 patients with sickle cell anemia, by comparing the cardio-pulmonary status of patients with
 sickle cell disease with and without pulmonary hypertension (2) to determine the relative
 acute vasodilatory effects of oxygen, intravenous prostacyclin, and inhaled nitric oxide on
 pulmonary artery pressures and other hemodynamic parameters in patients with secondary
 pulmonary hypertension and sickle cell anemia, (3) to determine the effects of two months of
 inhaled nitric oxide on pulmonary artery pressures, other hemodynamic parameters, exercise
 tolerance, and symptoms in this patient population, and (4) to determine the effects of three
 months of exchange transfusion on pulmonary artery pressures, other hemodynamic parameters,
 exercise tolerance, and symptoms in patients who do not receive or fail to respond to NO
 therapy.
-  INCLUSION CRITERIA

 For Stage I for Pulmonary Hypertension Subjects:

 Male or female, 18 years of age or older.

 Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S
 beta-halassemia genotype is required).

 Hematocrit greater than 18% (with an absolute reticulocyte count greater than 100,000/ml if
 hematocrit is 18-24%).

 Mild to severe pulmonary hypertension with systolic pulmonary artery pressures greater than
 or equal to 30 mm Hg (tricuspid regurgitant velocity greater than 2.5 m/sec, assuming right
 atrial pressure greater than 5 cm H20) or right ventricular enlargement. We will compare
 these studies to a control group of sickle cell patients that do not have pulmonary
 hypertension.

 For Stage I Controls:

 Males or females, 18 years of age or older.

 Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S
 beta-halassemia genotype is required).

 Hematocrit greater than 18% (with an absolute reticulocyte count greater than 100,000/ml if
 hematocrit is 18-24%).

 Tricuspid regurgitant velocity less than or equal to 2.4 m/sec, matched for age, gender,
 hydroxyurea therapy status and fetal hemoglobin levels with the pulmonary hypertension
 subjects.

 For Stage II:

 Male or female, 18 years of age or older.

 Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S
 beta-thalassemia genotype is required).

 Hematocrit greater than 18% (with an absolute reticulocyte count greater than 100,000/ml if
 hematocrit is 18-24%).

 Mild to severe pulmonary hypertension with systolic pulmonary artery pressures greater than
 or equal to 30 mm Hg (tricuspid regurgitant velocity greater than 2.5 m/sec, assuming right
 atrial pressure greater than 5 cm H20) or right ventricular enlargement.

 For Stage III:

 Male or female, 18 years of age or older.

 Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S
 beta-thalassemia genotype is required).

 Hematocrit greater than 18 % (with an absolute reticulocyte count greater than 100,000/ml
 if hematocrit is 18-24%).

 Able to walk at least 100 m in six minutes at baseline.

 Mild to severe pulmonary hypertension with mean pulmonary artery pressures greater than or
 equal to 25 mm Hg, measured by pulmonary artery catheterization.

 Pulmonary artery wedge pressure or left ventricular end-diastolic pressure less than or
 equal to 18 mm Hg or echocardiographic criteria to exclude left ventricular dysfunction.

 EXCLUSION CRITERIA

 For Stage I

 Current pregnancy or lactation

 For Stage II

 Current pregnancy or lactation

 Any of the following medical conditions:

 Significant renal insufficiency (patient on hemodialysis or estimated creatinine clearance
 less than 30% of normal; Stroke within the last six weeks; New diagnosis of pulmonary
 embolism within the last three months; History of retinal detachment.

 Hematocrit less than 18 % will not be eligible for the study; may return for evaluation at
 a later date.

 Patients taking prostacyclin (inhaled or intravenous) will be excluded from the study.
 Patients taking calcium channel blockers will be allowed to participate provided they are
 on a stable dose for greater than one month.

 For Stage III

 Current pregnancy or lactation

 Any of the following medical conditions:

 Significant renal insufficiency (patient on hemodialysis or estimated creatinine clearance
 less than 30%of normal; Stroke within the last six weeks; Left ventricular end-diastolic
 pressure greater than or equal to 18 mm Hg (determined by the pulmonary artery occlusion
 pressure) or echocardiographic criteria for left ventricular dysfunction; New diagnosis of
 pulmonary embolism within the last three months; History of retinal detachment;

 Hematocrit less than 18 % will not be eligible for the study; may return for evaluation at
 a later date.

 Patients taking prostacyclin (inhaled or intravenous) will be excluded from the study.
 Patients taking calcium channel blockers will be allowed to participate provided they are
 on a stable dose for greater than one month.

 Patients who are in other research studies for the treatment of pulmonary hypertension or
 who are on treatment specific for pulmonary hypertension will be excluded from stage III of
 this study.