Intravenous Norepinephrine for Orthostatic Hypotension

Objective:

Patients with chronic autonomic failure (CAF) often have disabling orthostatic hypotension
(OH). In CAF, OH results from deficient baroreflex-mediated release of norepinephrine (NE)
from sympathetic nerves. In patients with pure autonomic failure (PAF) or Parkinson disease
(PD) with OH, cardiac and extra-cardiac noradrenergic denervation exacerbates effects of
baroreflex failure. OH in CAF patients is often associated with supine hypertension, which
can be severe. Drugs to treat OH worsen supine hypertension. Therefore, the combination of
OH with supine hypertension poses a difficult therapeutic challenge. This protocol is a
first step toward development of a prosthetic baroreceptor system to maintain blood
pressure during orthostasis without worsening supine hypertension. In patients with PAF or
PD+OH NE is infused i.v. at doses titrated individually to maintain blood pressure during
head-up tilt at increasing angles from horizontal. Blood pressure is monitored continuously
directly via an intra-arterial catheter. Because of the phenomenon of denervation
supersensitivity, we anticipate that patients with OH associated with sympathetic
noradrenergic denervation, as in PAF and PD, should be especially responsive to i.v.
norepinephrine.

Study Population:

Patients with Parkinson disease and orthostatic hypotension or with pure autonomic failure.

Design:

This is a placebo controlled study that consists of two experimental days per participant.
On a day before the day of norepinephrine (NE) infusion, the patient undergoes head-up
tilting (typically at 15, 30, 45, and 60 degrees from horizontal) while blood pressure is
monitored. Tilt angles are increased until the patient has orthostatic symptoms, systolic
pressure decreases to less than 90 mm Hg, or systolic pressure decreases by more than 80 mm
Hg. On the day of NE infusion patients, receive NE and placebo with the sequence of
treatments randomized. If the patient has severe supine hypertension (more than 200 mm Hg
systolic), then NE is infused beginning with the patient at whatever tilt angle is required
for baseline pressure to be less than 200 mm Hg. NE is infused at doses titrated to keep
directly recorded systolic blood pressure at or above the baseline value during exposure to
higher tilt angles. When placebo is given, angles of tilt are increased until the patient
has orthostatic symptoms, systolic pressure decreases to less than 90 mm Hg, or systolic
pressure decreases by more than 80 mm Hg.

Outcome Measures:

The extent to which NE infusion can maintain blood pressure is tested by comparison of the
fractional changes in systolic blood pressure at the same tilt angles during NE infusion vs.
placebo infusion.

Primary:

1. Blood pressures (systolic, diastolic, mean)

2. Symptoms of orthostatic intolerance

Secondary:

1. Hemodynamics (e.g., total peripheral resistance)

2. Arterial plasma levels of norepinephrine and related neurochemicals

Comparison:

Patients undergo head-up tilt at the same angles to verify orthostatic hypotension if
norepinephrine is not infused.

Participating Sites:

The study is done in the NIH Clinical Center in Bethesda, MD.

Contact Information:

The Principal Investigator is David S. Goldstein, MD PhD, Chief, Clinical Neurocardiology
Section, CNP/DIR/NINDS/NIH, phone 301-496-2103, e-mail goldsteind@ninds.nih.gov. The contact
for patient care coordination is Tereza Jenkins, phone 301-496-1115, e-mail
jenkinst@ninds.nih.gov. The research contact (e.g., for database coordination) is Sandra
Pechnik, phone 301-435-5166, e-mail pechniks@ninds.nih.gov.

- INCLUSION CRITERIA:

A candidate subject is eligible for inclusion if he or she satisfies all of the following
criteria:

Aged 18 years or over.

A confirmed diagnosis of neurogenic orthostatic hypotension related to Parkinson disease
or pure autonomic failure.

Able to provide informed consent

EXCLUSION CRITERIA:

A candidate subject is ineligible for inclusion if he or she satisfies any of the
following criteria:

Receiving medications expected to augment or attenuate blood pressure responses to i.v.
norepinephrine (such as tricyclic antidepressants or alpha-adrenoceptor blockers).

Has heart block (unless a functioning cardiac pacemaker is in place or the patient is
cleared by a cardiologist).

Raynaud's phenomenon or other findings in the medical history suggest a tendency to
vasospasm.

History of myocardial infarction or current evidence of symptomatic congestive heart
failure or symptomatic coronary ischemia.

Current evidence of ventricular arrhythmias or frequent premature ventricular
contractions.

Renal failure.

History of mesenteric ischemia.

History of cerebrovascular ischemic disease, unless corrected (e.g., by stent).

Technical or medicinal limitations that obviate safe placement of arm intravenous and
intra-arterial catheters for drug infusion and blood drawing. Examples of medicinal
limitations are required daily aspirin ingestion and previously documented lidocaine
allergy.

Pregnant or lactating or a female of child bearing potential who refuses to have a blood
test for pregnancy. (Urine pregnancy tests can yield false-negative results, due to
incorrect test preparation, urine that is too dilute, or interference by several
medications. We have experience with the NIH Clinical Pathology Department not calling a
urine test for pregnancy positive or negative because the urine was dilute. Serum
pregnancy tests do not have these limitations.)

Unable to tolerate lying supine on a tilt table.

Closed angle glaucoma.