Propranolol to Treat Fainting in Children With Sympathoadrenal Imbalance
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Syncope
Intervention: Propranolol (Drug)
Phase: Phase 2
Sponsored by: National Institute of Neurological Disorders and Stroke (NINDS)
This study will examine the effectiveness of the drug propranolol in preventing fainting in
patients with sympathoadrenal imbalance (SAI). SAI is a particular pattern of nervous system
and chemical responses in which the blood vessels in skeletal muscles do not remain
constricted appropriately during standing for a long time. This can lower blood pressure and
cause fainting. Propranolol (Inderal® (Registered Trademark)) is a Food and Drug
Administration-approved drug that belongs to a class of drugs called beta-blockers. These
drugs slow the heart rate and maintain blood pressure in certain situations.
Children between 10 and 17 years of age with frequent fainting or near-fainting due to SAI
may be eligible for this study. Children must experience severe dizzy episodes at least once
every 2 months or fainting episodes at least once every 4 months. The condition must be
severe enough to affect the child's quality of life or to have forced the child to alter his
or her life routines to accommodate to the illness. Screening includes a tilt table test,
described below, to determine if the child has a particular chemical pattern in the blood.
Children enrolled in the study take propranolol pills in increasing doses during the first
week of the study to determine the proper dose for the individual. Then, the drug is stopped
until the experimental phase of the study begins. In this phase, children are randomly
assigned to take either propranolol or placebo (a look-alike pill with no active ingredient)
for a maximum of 3 days. On the fourth day, the child undergoes a tilt table test to
determine whether the treatment affects his or her ability to tolerate tilt. For this test,
the child lies on a padded table with a motorized tilt mechanism that can move the child from
a flat position to an upright position in about 10 seconds. The child remains upright for up
to 40 minutes while the following measurements are taken:
- Blood sampling: Blood is drawn through a catheter (thin plastic tube) placed in an arm
vein. This allows repeated sampling without repeated needle sticks. Samples are
collected before starting the tilt test, about every 4 minutes during the test,
immediately when a drop in blood pressure is detected or symptoms develop, and after 10
minutes of recovery lying flat. A maximum of 12 samples are collected for each tilt
- Physiologic measurements: Blood pressure, heart rate, and electrocardiogram (EKG) are
measured continuously during the tilt test session, and blood flows and skin electrical
conduction are measured intermittently. Blood flow is measured using sensors applied to
the skin and a blood pressure cuff around the limb. For skin blood flow measurements, a
laser beam scans the skin surface. The skin electrical conduction test measures how well
the skin conducts electricity. This is measured through sensors placed on the tips of
two fingers. Respiration and breathing rate are monitored by an elastic cloth band
around the chest.
- Self-report questionnaires: Patients or their parents complete a questionnaire about the
child's symptoms before and during treatment.
The effects of the test drug are allowed to wear off for up to 1 week, after which the entire
tilt test procedure is repeated. Patients who were given propranolol for the first test
session take placebo for the repeat session, and those who were given placebo take
Official title: Propranolol for Syncope With Sympathoadrenal Imbalance in Children
Study design: Treatment, Safety/Efficacy Study
Objectives: This protocol is to evaluate treatment with oral propranolol for a particular
form of neurocardiogenic syncope (NCS), characterized by a neuroendocrine pattern called
"sympathoadrenal imbalance" (SAI), in children. In SAI, plasma adrenaline levels increase
progressively and to a greater extent than do norepinephrine levels, before syncope. The SAI
pattern is associated with skeletal muscle vasodilation. We hypothesize that increased
occupation of beta-2 adrenoceptors in skeletal muscle by high circulating adrenaline levels
precipitates the neurocirculatory positive feedback loop that leads to NCS.
Study Population: Patients 10-17 years old with a history of NCS.
Design: In a randomized, crossover-design, placebo-controlled, double-blind trial, we test
the above hypothesis by using the non-selective beta-adrenoceptor blocker, propranolol. We
predict that in patients with previously documented SAI and tilt-evoked NCS, propranolol
treatment will improve orthostatic tolerance during follow-up tilt table testing.
Outcome Measures: The primary outcome measure will be whether propranolol therapy can
prevent tilt induced syncope; or significant hypotension and/or bradycardia preceding
development of clinical symptoms (greater than or equal to 20 mm Hg decrease in blood
pressure or heart rate less than 40 beats/min). Secondary dependent measures that will be
assessed are occurrence of duration of tilt tolerance (if tilt induced symptoms are
provoked), hemodynamic and neurochemical indices of SAI, and patient questionnaire reports.
Minimum age: N/A.
Maximum age: N/A.
Subjects are patients referred for evaluation of chronic orthostatic intolerance. Patients
enter into the therapeutic trial after they are determined to have NCS with SAI in a
screening evaluation. Participation in this protocol is offered to individuals 10-17 years
of age, independently of gender, race, ethnicity, religion, or any other demographic or
sociopolitical classifications. To be eligible to enter this study, the patient must have
a minimum frequency of pre-syncope of at least 1 event/2 months, or syncope of at least
once/4 months. The severity of the symptoms should be of such severity as to alter the
individual's quality of life or routines of life.
Age: Minors younger than 10 years old and pregnant female subjects between 10 and 17 years
of age will be excluded.
Risk: A candidate subject is excluded if, in the judgment of the Principal Investigator,
protocol participation would place the subject at substantially increased acute medical
risk. This includes the risk associated with air travel to the NIH. A candidate subject
is excluded if, in the opinion of the Principal Investigator, 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 history of asthma or chronic
obstructive pulmonary disease requiring bronchodilators, hepatic or renal failure,
atrioventricular block of any degree, bradycardia, symptomatic congestive heart failure,
severe anemia, psychosis, refractory ventricular arrhythmias, insulin-dependent diabetes
mellitus, or psychiatric disorders requiring continuous drug treatment. Patients with
known allergy or hypersensitivity to propranolol are excluded from this study. A positive
HIV test result does not necessarily exclude a patient from participating. If a female
subject becomes pregnant during the study, she will be excluded from further participation
in the study.
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.
Patients who must take medications daily in the following categories are excluded:
anticoagulants, tricyclic antidepressants, barbiturates, aspirin, acetaminophen, insulin,
and bronchodilators. Patients are not to discontinue any medications before the patient or
the patient's doctor discusses this with the Principal Investigator, an Associated
Investigator, or Research Nurse. If it is decided that discontinuing medications would be
unsafe, then the patient is excluded from the study.
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. For
many herbal medicines or dietary supplements, the mechanisms of action and therefore the
possible effects on the experimental results are unknown. In cases where the subjects wish
to continue their herbal medicines or dietary supplements while in study, and search the
available medical literature fails to identify effects that are known or expected to
interfere with the experimental results, then the subjects may participate.
Practical Limitations: Patients in whom we feel it would be difficult to technically carry
out the testing procedures are excluded.
Pregnancy: Pregnant or lactating females of child-bearing potential are excluded. A blood
test pregnancy will be conducted in all females of childbearing potential, before intake
evaluation and also before each drug treatment phase. During the course of the protocol,
patients who are of childbearing potential will be advised to practice adequate
contraception (birth control pills, Depo-Provera, or implanted intrauterine device), if
sexually active. If during the course of this study, a minor patient is found to have a
positive pregnancy test, she will be asked confidentially whether she has had any recent
sexual activity that could have resulted in the test being positive. In agreement with
current legal statutes, the minor patient will be told confidentially that she is pregnant.
She will be encouraged to share this information with her parents. By current legal
statutes, we will not directly divulge this information to her parents. The pregnant minor
subject will also be told that further participation in the study is a protocol violation
(because of possible adverse risks to the unborn fetus), and she will be terminated from
continued participation in the protocol.
Locations and Contacts
National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland 20892, United States
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Goldstein DS, Holmes C, Frank SM, Dendi R, Cannon RO 3rd, Sharabi Y, Esler MD, Eisenhofer G. Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes. Circulation. 2002 Oct 29;106(18):2358-65.
Jacobs MC, Goldstein DS, Willemsen JJ, Smits P, Thien T, Dionne RA, Lenders JW. Neurohumoral antecedents of vasodepressor reactions. Eur J Clin Invest. 1995 Oct;25(10):754-61.
Starting date: October 2004
Ending date: March 2005
Last updated: March 3, 2008