This study will conduct tests with patients with primary chronic orthostatic intolerance
(COI) to learn more about this disorder of the autonomic nervous system.
Healthy normal volunteers and patients 18 years of age and older with COI may be eligible
for this study. Participants undergo one or more of the following tests and procedures:
- Blood studies, including arterial catheter insertion to measure blood pressure and
collect arterial blood samples, blood flow studies using sensors applied to the skin
and a pressure cuff around a limb, blood volume studies using injection of
radioactively labeled human serum albumin and gene studies to look for genetic
abnormalities associated with certain proteins.
- Imaging studies, including CT scan of the adrenal glands, heart ultrasound, and PET
- Microdialysis to measures levels of chemicals in the body fluid of certain tissues. A
thin tube is inserted into the skin and a solution is passed through it. Chemicals in
the body tissues enter the solution in the tube. The solution is collected and the
chemical levels are measured.
- Neck suction. Neck suction is applied to test a reflex the brain uses to regulate blood
- Perometry. Limb volume is measured using an infrared light that moves up the limb.
- Quantitative sudomotor axon reflex test to evaluate an aspect of autonomic nervous
system function. A small amount of a brain chemical (acetylcholine) is applied to the
skin with a tiny amount of electricity, and the sweat in a nearby patch of skin is
- Skin electrical conduction test using sensors on the skin to measure sweat production.
- Skin and core temperature measurements using sensors on the skin and in the ear canal.
- Tilt table test. The subject lies on a table, secured with 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 to collect blood samples
and give drugs. Another catheter is placed in an artery to draw blood and monitor blood
pressure. The subject is given an infusion of norepinephrine and epinephrine, and
baseline measures and blood samples are taken. The table is tilted upright and more
measurements and blood samples are taken at intervals for up to 30 minutes. The table
is returned to a horizontal position and additional measurements and samples may be
Drugs may be administered during the tests, including acetylcholine, epinephrine, and
norepinephrine, radioactive chemicals used in imaging studies, and drugs that affect blood
vessels, heart rate, and force of heart contractions.
This protocol is to identify and characterize distinct types of chronic orthostatic
intolerance (COI). COI can be a 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.
- INCLUSION CRITERIA:
The subjects are patients with COI and adult healthy 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
The subjects in the second off-site study are family members of the identified proband.
Participation in this protocol is offered to people 18 years old or older, independently
of gender, race, ethnicity, religion, or any other demographic or sociopolitical
In the second off-site study, participation is also 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.
Age: Minors younger than 18 years old are excluded, except for the off-site study.
Advanced age does not constitute an exclusion criterion. For subjects more than 55 years
old, carotid Doppler studies are done, and subjects with significant carotid disease
(stenosis by atherosclerosis) are excluded. In the off-site study, minors younger than 10
years old are excluded. For the second off-site study, minors younger than 10 years old
are excluded. Advanced age does not constitute an exclusion criterion. Except for the
second off-site study, people less than 18 years old are excluded.
Risk: A candidate subject is excluded if, in the judgment of the Principal Investigator or
Clinical Director, protocol participation would place the subject at substantially
increased acute medical risk. This includes the risks associated with air travel to the
NIH. A candidate subject is excluded if, in the opinion of the Principal Investigator or
Clinical Director, the medical risk outweighs the potential scientific benefit.
Disqualifying Conditions: A candidate subject is excluded if there is a disqualifying
condition. Examples of disqualifying conditions are hepatic or renal failure, a history of
tachyarrhythmias, symptomatic congestive heart failure, severe anemia, psychosis,
refractory ventricular arrhythmias, symptomatic coronary heart disease, diabetes mellitus,
hyperthyroidism, and allergy or sensitivity to iodinated contrast media or any of the
planned drugs. A positive HIV rest result does not necessarily exclude a patient from
Medications: A candidate subject is excluded if clinical considerations require that the
patient continue treatment with a drug likely to interfere with the scientific results.
Examples are tricyclic antidepressants, anticoagulants, beta-adrenoceptor blockers,
phenothiazines, barbiturates, monoamine oxidase inhibitors, acetaminophen, and
alpha-adrenoceptor agonists or antagonists. Patients on one or more of these drugs are not
excluded, if the drugs are tapered and discontinued before undergoing the clinical
laboratory testing. Patients are not to discontinue any medications before the patient or
the patient's doctor discusses this with the Principal Investigator. If it is decided that
discontinuing medications would be unsafe, then the patient is excluded from the study.
Patients with known or suspected allergy or hypersensitivity to any test drug are
excluded. Patients unable to discontinue nicotine or alcohol for 24 hours prior to
evaluation are excluded.
Patients with chronic orthostatic intolerance often take several medications that could
interfere with the scientific results of this protocol. Temporary discontinuation of
medications as outpatients, even with the approval of the referring physician, introduces
some risk. To maximize patient safety, we may admit patients for monitoring as inpatients
while medications are tapered or stopped.
In the second off-site study, subjects are tested while on their usual medications.
Herbal Medicines and Dietary Supplements: Certain herbal medicines or dietary supplements
are known or suspected to interfere with the experimental results, and such herbal
medicines or dietary supplements must be discontinued before enrollment in the study. In
cases where the subjects wish to continue their herbal medicines or dietary supplements
while on study, and search of the available medical literature fails to identify effects
that are known or expected to interfere with the experimental results, then the subjects
may participate. Subjects in the off-site study may continue their herbal medicines or
Practical Limitations: Patients in whom we feel it would be difficult to insert a catheter
into a vein are excluded. Subjects who are not expected clinically to tolerate lying still
during the procedures are excluded. In the second off-site study, if an i.v. cannot be
placed, or the subject refuses to have an i.v. placed then a DNA sample may be obtained by
buccal smear or obtaining saliva.
Pregnancy: Pregnant or lactating women are excluded. In the second off-site study,
pregnancy is not an exclusion criterion.
The Investigators may also exclude a subject from further participation, such as in the
event of known or suspect falsification of medical history information or refusal to
undergo planned tests or procedures, without loss of benefits to which the subject was