This study will conduct laboratory tests and administer various drugs to patients with primary chronic orthostatic intolerance (COI) to learn more about this disorder. COI is a problem of the autonomic nervous system, which regulates many automatic body functions, such as blood pressure and pulse rate, and tolerating simply standing up. Healthy subjects will be studied as well as patients, to compare test results in both groups.

Healthy normal volunteers and patients 18 years of age and older with COI may be eligible for this study. Candidates will be screened with a medical history, physical examination, and a special test to measure blood pressure and pulse rate while lying down and after standing for up to 5 minutes. Blood samples will be collected during this test through a catheter (plastic tube) placed in an arm vein. In addition, those enrolled in the study will undergo one or more of the following tests and procedures:

- Arterial catheter: A catheter is inserted into an artery in the elbow crease or the wrist to continuously measure blood pressure and to collect arterial blood samples.

- Blood drawing: Blood samples are collected through a catheter in an arm artery.

- Blood flow studies: Sensors are applied to the skin of the leg or arm and a blood pressure cuff is placed around the limb and inflated and deflated several times. For skin blood flow measurements, a laser light is shined on the skin.

- Blood volume: Blood volume is measured by drawing blood through a catheter following injection of a tiny amount of radioactively labeled human serum albumin (a natural protein in the blood).

- Computed tomography (CT) scan of the adrenal glands: The subject is placed in a doughnut-shaped scanner for several minutes while the adrenal glands (glands that sit atop the kidneys) are scanned.

- Genetic testing (COI patients only): A blood sample is collected for DNA studies to look for genetic abnormalities associated with certain proteins. The information may help explain how changes in genes may cause COI symptoms and lead to improved treatment or prevention.

- Echocardiogram: This ultrasound test uses sound waves to produce images for examining heart function.

- Electrocardiogram (EKG): This test uses electrodes attached to the skin to measure the electrical activity of the heart.

- Microdialysis: This test measures levels of chemicals in the body fluid of particular tissues, such as fatty tissue under the skin. After numbing the skin with an anesthetic, a thin tube is inserted into the skin. A solution similar to body fluid is passed through the tube, and chemicals in the body tissues enter the solution in the tube. The solution in the tube is collected and the chemical levels are measured.

- Neck suction: Neck suction is applied to test a particular reflex the brain uses to regulate blood pressure.

- Positron emission tomography (PET) scanning: This procedure is similar to a CT scan (see above), but uses an injection of a radioactive drug to produce images of body organs.

- Perometry: Limb volume is measured using an infrared light that moves up the limb over several seconds, beginning as soon as the subject stands up and then for up to 30 minutes of standing.

- Quantitative sudomotor axon reflex test (QSART): This is a diagnostic test of a particular aspect of autonomic nervous system function. A small amount of a brain chemical called acetylcholine is applied to the skin with a tiny amount of electricity. The sweat in a nearby patch of skin is measured by following the amount of humidity in a chamber applied to the skin.

- Skin electrical conduction test: This is a test of sweat production. Sweat conducts electricity, so changes in sweating can be measured by the resistance of the skin to the flow of electricity. This is done with sensors placed on the skin.

- Skin and core temperature: Skin temperature is measured with sensors placed on the skin, and body core temperature is measured with sensors in a cotton ball that is placed in the ear canal against the eardrum.

- Tilt table test: This test evaluates the subject's ability to tolerate tilt. The subject lies on a padded table, secured with Velcro straps around the chest and legs. Sensors are placed on the arms and chest to monitor blood pressure, pulse rate, and heart rhythm. A catheter is placed in a vein in each arm, one for drawing blood samples and one for giving drugs. Another catheter is placed in an artery for drawing blood and monitoring blood pressure. The subject is given an infusion of norepinephrine and epinephrine, and baseline measures and blood samples are taken. Then the table is tilted to an upright position and more measurements and blood samples are taken at intervals for up to 30 minutes. The table is brought back to a horizontal position and additional measurements and samples may be taken.

Various drugs may be administered during the above tests, including chemical messengers, such as acetylcholine, epinephrine, and norepinephrine; radioactive chemicals used in imaging studies, and drugs that affect blood vessels, heart rate, and force of heart contractions.

Condition	Treatment or Intervention
Syncope	Drug: 18F-Fluorodopamine  Drug: 13N-Ammonia  Drug: Tyramine  Drug: Acetylcholine

Further Study Details: 

Expected Total Enrollment:  175

This protocol is to identify and characterize distinct types of chronic orthostatic intolerance (COI). COI can be manifestation of primary chronic autonomic failure, which is covered under a separate protocol. The present protocol concerns patients with COI who under resting conditions have intact sympathetic neurocirculatory function. COI can reflect different pathophysiologic mechanisms; until now, few studies have attempted to distinguish these mechanisms in individual patients. We hypothesize that results of clinical assessment and physiologic, chemical, pharmacologic, and imaging tests will reveal internally consistent patterns that distinguish particular forms of COI. We wish to determine the relative frequencies of these forms in a referral population. The first phase of testing is to identify sympathetic neurocirculatory failure, baroreflex failure, and secondary causes of COI (hypovolemia, excessive orthostatic venous pooling, or excessive orthostatic extravasation). In a subsequent inpatient phase, tilt table testing is done, with concurrent hemodynamic and chemical measurements, to confirm subtypes of postural tachycardia syndrome and neurocardiogenic syncope. The results of these evaluations will be used for stratification of specific, pathophysiologically defined diagnostic groups for therapeutic protocols. In an off-site study, we will evaluate members of a large family where COI seems to be transmitted as an autosomal dominant trait.

Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

INCLUSION CRITERIA:
The subjects are patients with COI and adult normal volunteers of similar age, gender, and body mass.
Participation in this protocol is offered to people 18 years old or older, independently of gender, race, age, ethnicity, religion, or any other demographic or sociopolitical classifications.
For the off-site study the subjects are family members of the identified proband. For the off-site study only, participation is offered to subjects 10 to 17 years old, provided that appropriate informed consent/assent has been given by the subject and his/her parent or guardian.
EXCLUSION CRITERIA:
Age. Minors younger than 18 years old are excluded.
Subjects with significant carotid disease (stenosis by atherosclerosis) are excluded.
For the off-site study only, minors younger than 10 years old are excluded.

Maryland
      National Institute of Neurological Disorders and Stroke (NINDS), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States

Study ID Numbers:  030314; 03-N-0314
Record last reviewed:  August 2, 2004
Last Updated:  November 23, 2004
Record first received:  September 29, 2003
ClinicalTrials.gov Identifier:  NCT00069693
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08