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 [email protected]. The contact for patient care coordination is Tereza Jenkins, phone 301-496-1115, e-mail [email protected]. The research contact (e.g., for database coordination) is Sandra Pechnik, phone 301-435-5166, e-mail [email protected].